Inhibition of OLIG2 activity

ABSTRACT

Described herein are urea compounds and pharmaceutical compositions containing such compounds, which inhibit the activity of Olig2. Also described herein are methods of using such Olig2 inhibitors, alone and in combination with other compounds, for treating cancer and other diseases. In particular the Olig2 inhibitors may be used to treat glioblastoma.

CROSS-REFERENCE

This application is a U.S. National Stage entry of InternationalApplication No. PCT/US2017/048716, filed Aug. 25, 2017, which claimsbenefit of U.S. Provisional Application No. 62/380,281, filed on Aug.26, 2016, each of which is herein incorporated by reference in theirentirety.

BACKGROUND OF THE INVENTION

Current brain tumor therapeutic agents, which are only able to extendmedian survival of patients by six months, cause significant systemictoxicity. This toxicity results in serious long term morbidity of thefew patients that survive, in terms of cognition, endocrine disorders,and motor effects. Currently brain tumors are essentially incurable witha median survival of fifteen months.

SUMMARY OF THE INVENTION

Described herein are compounds of Formula (I), (II), (III), or (IV)(hereinafter “compounds of Formula (I), (II), (III), or (IV)”),compositions that include such compounds, and methods of use thereof,for inhibition of Olig2 activity.

In one aspect, described herein is a compound of Formula (I):

wherein:

is naphthalene or a bicyclic C₅-C₉heteroaryl, wherein

is unsubstituted or substituted by 1, 2, or 3 R₁ groups;

-   -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₉heteroaryl; R₂ and R₃ are each        independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, or        C₂-C₇heterocycloalkyl; or R₂ and R₃ are taken together to form a        5- or 6-membered heterocyclic ring;    -   R₄ and R₅ are independently H, halogen, —CN, —OH, —CF₃,        substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆alkoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₉heteroaryl;    -   R₆ is H, unsubstituted C₁-C₆alkyl, C₁-C₆haloalkyl,        —(C(R₁₄)(R₁₅))_(m)R₁₇, —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂),        —(C(R₁₄)(R₁₅))_(m)OR₁₃, —(C(R₁₄)(R₁₅))_(n)R₁₆, or —OR₂₂;    -   each R₈ is independently H or substituted or unsubstituted        C₁-C₆alkyl;    -   each R₉ is independently substituted or unsubstituted        C₁-C₆alkyl;    -   R₁₀ is H or unsubstituted C₁-C₄alkyl;    -   R₁₁ is H, substituted or unsubstituted C₁-C₆alkyl, —C(═O)R₁₉, or        —S(═O)₂R₁₉;    -   R₁₂ is H or substituted or unsubstituted C₁-C₆alkyl;    -   R₁₃ is H or substituted or unsubstituted C₁-C₆alkyl;    -   each R₁₄ and R₁₅ is each independently H, halogen, or        substituted or unsubstituted C₁-C₆alkyl;    -   R₁₆ is substituted or unsubstituted C₂-C₇heterocycloalkyl or        —C(═O)N(Rig)₂;    -   R₁₇ is —C(═O)R₂₀, —CO₂R₂₁, —C(═O)N(R₂₁)₂, or substituted or        unsubstituted C₂-C₉heteroaryl;    -   each R₁₈ is independently H, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl,        or substituted or unsubstituted C₃-C₈cycloalkyl; or    -   two R₁₈ are taken together to form a heterocycloalkyl ring;    -   R₁₉ is substituted or unsubstituted C₁-C₆alkyl;    -   R₂₀ is substituted or unsubstituted C₁-C₆alkyl;    -   each R₂₁ is independently H, or substituted or unsubstituted        C₁-C₆alkyl; or two R₂₁ are taken together to form a        heterocycloalkyl ring;    -   R₂₂ is H, or substituted or unsubstituted C₁-C₆alkyl;    -   m is 2-6; and    -   n is 1-5; or    -   a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment is a compound of Formula (I) wherein R₂ and R₃ areeach independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(I) wherein R₂ and R₃ are each H. In another embodiment is a compound ofFormula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). In anotherembodiment is a compound of Formula (I) wherein R₁₂ is H. In anotherembodiment is a compound of Formula (I) wherein R₁₂ is unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (I) whereinR₁₂ is —CH₃. In another embodiment is a compound of Formula (I) whereinR₁₁ is —C(═O)R₁₉. In another embodiment is a compound of Formula (I)wherein R₁₁ is —C(═O)R₁₉ and R₁₉ is unsubstituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (I) wherein R₁₁ is —C(═O)R₁₉ and R₁₉is —CH₃. In another embodiment is a compound of Formula (I) wherein R₁₁is —S(═O)₂R₁₉. In another embodiment is a compound of Formula (I)wherein R₁₁ is —S(═O)₂R₁₉ and R₁₉ is unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (I) wherein R₁₁ is—S(═O)₂R₁₉ and R₁₉ is —CH₃. In another embodiment is a compound ofFormula (I) wherein R₁₁ is unsubstituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (I) wherein R₁₁ is —CH₃. In anotherembodiment is a compound of Formula (I) wherein R₁₁ is substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (I) whereinR₁₁ is C₁-C₆alkyl substituted with —OH. In another embodiment is acompound of Formula (I) wherein R₁₁ is H. In another embodiment is acompound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is H. In another embodiment is a compoundof Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ issubstituted or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (I) wherein R₆ is —(C(R₁₄)(R₅))_(m)R₇. In anotherembodiment is a compound of Formula (I) wherein R₁₇ is —C(═O)R₂₀. Inanother embodiment is a compound of Formula (I) wherein R₁₇ is —C(═O)R₂₀and R₂₀ is unsubstituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (I) wherein R₁₇ is —CO₂R₂₁. In another embodiment is acompound of Formula (I) wherein R₁₇ is —CO₂R₂₁ and R₂₁ is H orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(I) wherein R₁₇ is —C(═O)N(R₂₁)₂. In another embodiment is a compound ofFormula (I) wherein R₁₇ is —C(═O)N(R₂₁)₂ and each R₂₁ is independently Hor unsubstituted C₁-C₆alkyl. In another embodiment is a compound ofFormula (I) wherein R₁₇ is substituted or unsubstituted C₂-C₉heteroaryl.In another embodiment is a compound of Formula (I) wherein m is 2. Inanother embodiment is a compound of Formula (I) wherein m is 3. Inanother embodiment is a compound of Formula (I) wherein m is 4. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(n)R₁₆. In another embodiment is a compound of Formula(I) wherein n is 1. In another embodiment is a compound of Formula (I)wherein R₁₆ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (I) wherein R₁₆ is—C(═O)N(R₁₈)₂. In another embodiment is a compound of Formula (I)wherein R₁₆ is —C(═O)N(R₁₈)₂ and each R₁₈ is independently H orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(I) wherein each R₁₄ and R₁₅ is each independently H, halogen, orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(I) wherein R₁₄ and R₁₅ are each H. In another embodiment is a compoundof Formula (I) wherein R₆ is —OR₂₂. In another embodiment is a compoundof Formula (I) wherein R₆ is —OR₂₂ and R₂₂ is H. In another embodimentis a compound of Formula (I) wherein R₆ is —OR₂₂ and R₂₂ isunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(I) wherein R₆ is H. In another embodiment is a compound of Formula (I)wherein R₆ is unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (I) wherein R₄ is H. In another embodiment is acompound of Formula (I) wherein R₄ is unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (I) wherein R₄ is —CH₃. Inanother embodiment is a compound of Formula (I) wherein R₄ isunsubstituted C₃-C₈cycloalkyl. In another embodiment is a compound ofFormula (I) wherein R₅ is H. In another embodiment is a compound ofFormula (I) wherein R₁₀ is H. In another embodiment is a compound ofFormula (I) wherein

is unsubstituted naphthalene or unsubstituted bicyclic C₅-C₉heteroaryl.In another embodiment is a compound of Formula (I) wherein

is selected from:

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another aspect, described herein is a compound of Formula (II):

wherein:

-   -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted phenoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl; or two R₁ are        taken together to form a substituted or unsubstituted        heterocyclic ring or a substituted or unsubstituted carbocyclic        ring;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₄ is H, halogen, —CN, —OH, —CF₃, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   R₆ is —OR₇;    -   R₇ is H, or substituted or unsubstituted C₁-C₆alkyl;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   each R₉ is independently substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₆-C₁₀aryl; and    -   n is 0-5; or    -   a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment is a compound of Formula (II) wherein R₂ and R₃ areeach independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(II) wherein R₂ and R₃ are each H. In another embodiment is a compoundof Formula (II) wherein R₇ is H. In another embodiment is a compound ofFormula (II) wherein R₇ is unsubstituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (II) wherein R₇ is —CH₃. In anotherembodiment is a compound of Formula (II) wherein R₄ is H. In anotherembodiment is a compound of Formula (II) wherein R₄ is unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (II) whereinR₄ is —CH₃. In another embodiment is a compound of Formula (II) whereineach R₁ is independently halogen, —OCF₃, —CF₃, —C(═O)R₉, unsubstitutedphenoxy, or unsubstituted C₆-C₁₀aryl. In another embodiment is acompound of Formula (II) wherein each R₁ is independently —OCF₃, —CF₃,—C(═O)R₉, unsubstituted phenoxy, or unsubstituted C₆-C₁₀aryl. In anotherembodiment is a compound of Formula (II) wherein n is 2. In anotherembodiment is a compound of Formula (II) wherein n is 1. In anotherembodiment is a compound of Formula (II) wherein n is 0.

In another aspect is a pharmaceutical composition comprising a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orprodrug thereof, and at least one pharmaceutically acceptable excipient.In another aspect is a pharmaceutical composition comprising a compoundof Formula (II), or a pharmaceutically acceptable salt, solvate, orprodrug thereof, and at least one pharmaceutically acceptable excipient.

In another aspect is the use of a compound of Formula (I), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof, for the formulation of amedicament for inhibiting the activity of Olig2 in a cell. The methodincludes contacting the cell with a compound of Formula (I) includingembodiments thereof.

In another aspect is the use of a compound of Formula (II), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof, for the formulation of amedicament for inhibiting the activity of Olig2 in a cell. The methodincludes contacting the cell with a compound of Formula (II) includingembodiments thereof.

In a further aspect is a method of treating a disease, disorder orcondition in a subject that would benefit from inhibition of Olig2activity comprising administering to the subject in need thereof acomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof. In some embodiments is amethod of treating a disease, disorder or condition in a subject thatwould benefit from inhibition of Olig2 activity comprising administeringto the subject in need thereof a composition comprising a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, or prodrugthereof; wherein the disease is cancer or Down's Syndrome.

In a further aspect is a method of treating a disease, disorder orcondition in a subject that would benefit from inhibition of Olig2activity comprising administering to the subject in need thereof acomposition comprising a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof. In some embodiments is amethod of treating a disease, disorder or condition in a subject thatwould benefit from inhibition of Olig2 activity comprising administeringto the subject in need thereof a composition comprising a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, or prodrugthereof; wherein the disease is cancer or Down's Syndrome.

In another aspect is a method for treating a disease in a subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein the disease is cancer orDown's Syndrome. In some embodiments is a method for treating cancer ina subject comprising administering to the subject in need thereof acomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof. In some embodiments is amethod for treating Down's Syndrome in a subject comprisingadministering to the subject in need thereof a composition comprising acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or prodrug thereof.

In another aspect is a method for treating a disease in a subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (II), or a pharmaceutically acceptablesalt, solvate, or prodrug thereof; wherein the disease is cancer orDown's Syndrome. In some embodiments is a method for treating cancer ina subject comprising administering to the subject in need thereof acomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof. In some embodiments is amethod for treating Down's Syndrome in a subject comprisingadministering to the subject in need thereof a composition comprising acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or prodrug thereof.

In another embodiment is a method for treating cancer in a subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein the cancer is brain cancer,glioblastoma multiforme, medulloblastoma, astrocytomas, brain stemgliomas, meningiomas, oligodendrogliomas, melanoma, lung cancer, breastcancer, or leukemia. In another embodiment is a method for treatingcancer in a subject comprising administering to the subject in needthereof a composition comprising a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or prodrug thereof, whereinthe cancer is brain cancer, glioblastoma multiforme, medulloblastoma,astrocytomas, brain stem gliomas, meningiomas, oligodendrogliomas,melanoma, lung cancer, breast cancer, or leukemia.

In another aspect is a method of inhibiting the activity of Olig2 in acell comprising contacting the cell with a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or prodrug thereof. Inanother aspect is a method of inhibiting the activity of Olig2 in a cellcomprising contacting the cell with a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or prodrug thereof.

In another aspect is the use of a compound of Formula (I), in themanufacture of a medicament for the treatment of a disease, disorder, orcondition that would benefit from inhibition of Olig2 activity. Inanother aspect is the use of a compound of Formula (II), in themanufacture of a medicament for the treatment of a disease, disorder, orcondition that would benefit from inhibition of Olig2 activity.

Other objects, features and advantages of the compounds, compositions,methods, and uses described herein will become apparent from thefollowing detailed description. It should be understood, however, thatthe detailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of thedisclosure will become apparent from this detailed description.

DETAILED DESCRIPTION

The compounds described herein are modulators or inhibitors of theneural and GBM (glioblastoma multiforme) stem cell transcriptionalrepressor OLIG2 (e.g. NM_005806, NP_005797 for human). OLIG2 (alsowritten herein as Olig2) is the oligodendrocyte transcription factor 2.This protein is a member of the bHLH (basic helix-loop-helix) family.The bHLH family is a family of transcription factors that contain thestructure motif characterized by two alpha helices connected by a loop.The transcription factors containing bHLH domains are generally dimeric.Generally one of the helices contains basic amino acid residues thatfacilitate binding to DNA. OLIG2 is normally restricted to the centralnervous system (CNS) in non-disease states, where it is an essentialregulator of progenitor cell fate. OLIG2 homodimerizes andhetereodimerizes with the E12 or E47 proteins to then bind and repressthe p21 gene promoter among other effects. P21 is a stem cell and tumorsuppressor, and is directly repressed by OLIG2. P21 is activated by thetumor suppressor p53. p53 occurs in the intact, wild type form in nearly70% of primary GBM patient samples. OLIG2 is highly expressed in alldiffuse gliomas, and is found in virtually 100% of GBM cells positivefor the CD133 stem cell marker. Importantly, OLIG2 is typically notfound in normal brain and in tissues outside the CNS unless they aremalignant, such as T-cell leukemia, melanoma, lung and breast cancer. Noother neural or glial marker gene, and no other transcriptionalrepressor displays as consistent a link to brain cancers. In contrast,membrane receptors (EGFR, PDGFR, etc) are not uniformly expressed amongpatients, and various approaches to targeting them has been met withlimited success in GBM treatment.

The expression of Olig2 in diffuse gliomas likely results from thetransformed stem cell origin of these tumors. It has been found that asmall cohort of the cells present in patient GBM expresses neural stemcell markers including CD133 and nestin, among others. The CD133(+)cells isolated from existing GBM are highly tumorigenic whenorthotopically implanted into mice. In one study, as few as 100 of theCD133(+) cells extracted from a patient GBM produced an invasive tumorwhen transplanted into the brain of a recipient mouse, while 100,000CD133(−) GBM cells were unable to generate a tumor. Consistent withthese findings, a strikingly high percentage of GBM occur in closeproximity to the neural stem cell germinal zones in the brain, i.e.,neural stem cells undergo malignant transformation and migrate somedistance from the germinal zones and establish a GBM.

Another significant finding with respect to GBM cancer stem cells (CSCs)is that the CD133(+) cells are significantly more resistant to radiationand cytotoxic agents used to treat GBM than the bulk of the tumor masswhich is comprised of CD133(−) cells. This suggests that conventionalradio/chemotherapy spares the CSCs within a GBM, and unless these cellsare targeted, the tumor invariably is resurgent, with lethal effect.Moreover, the very few patients that survive GBM suffer lifelongmorbidity from chemo- and radio-toxicity, in terms of cognition,endocrine balance, and other functions.

Olig2 is highly expressed in GBM CSCs, but is only expressed in lowlevels by normal brain and is not detected in tissues outside thenervous system. Olig2 inhibitors would offer a therapeutic marginsuperior to conventional chemotherapy. Low systemic toxicity would bemuch more compatible with long-term clinical management of GBM than isthe case with currently used treatment approaches.

High rates of mortality for patients with brain cancers make thisdisease a leading cause of cancer related death in men, women andchildren. Primary brain tumors are actually the most common solid tumorof childhood and the second leading cause of cancer death afterleukemia. The toxicity of current treatments causes serious life-longmorbidity in the few patients that survive. The development of smallmolecule, orally available drugs with low toxicity effective in braincancers would represent a significant advance. Moreover, the compoundsmay also be effective in other cancers that are stem cell driven andwhich highly express Olig2. These cancers include T-cell leukemias, skincancers, small cell lung cancers, and breast cancers. Moreover, thesecancers often metastasize to the brain. This would be relevant tomillions of patients worldwide.

In some embodiments described herein, are small molecules that inhibitOlig2 which is a transcription factor critical for survival andproliferation of glioblastoma and other brain cancers, i.e.,medulloblastoma, astrocytomas, brain stem gliomas, meningiomas, andoligodendrogliomas. Olig2 especially is detected primarily in the brain,generally not outside the nervous system, and it is highly expressed inglioblastoma tumors. This means that Olig2 inhibition should haverelatively low toxicity to a patient. Olig2 is also over-expressed inmelanomas, lung cancers, breast cancer and T-cell leukemias, so an Olig2inhibitor may also be applicable to the treatment of these cancers.

No other transcription factor or marker displays as consistent a link tobrain cancer as does Olig2, so Olig2 inhibition should compare favorablyto other signaling pathway inhibitors in glioblastoma. Olig2 is a robusttarget in that the hinge region of its dimerization loop is uniquecompared to other proteins of its class (basic helix-loop-helixproteins).

The Olig2 targeted inhibitors described herein should prove unique interms of efficacy and toxicity.

The existing agents, therapeutics, and methods used to treat braincancers include Temozolomide (TMZ-Temodar), radiation, cyclophosphamide,carmustine, carboplatin, and occasional supplementation with Avastin.All these are only somewhat effective standard brain cancer therapeuticagents, and they are very toxic. No brain cancer stem cell inhibitorscurrently exist for brain tumors.

In another aspect, methods of inhibiting the activity of OLIG2 areprovided. The methods include contacting an Olig2 protein with aneffective amount of a compound provided herein (e.g., a compound ofFormula (I), (II), (III), or (IV). The compound may have the structureof the Formulae provided herein (or any of the embodiments thereofdescribed above). In some embodiments, the methods of inhibiting a Olig2protein are conducted within a cell. Thus, in certain embodiments,methods of inhibiting the activity of Olig2 within a cell are provided.The method includes contacting a cell with an effective amount of acompound provided herein. The compound may have the structure of theFormulae provided herein (or any of the embodiments thereof describedabove). In some embodiments, the cell is a prokaryote or eukaryote. Thecell may be a eukaryote (e.g. protozoan cell, fungal cell, plant cell oran animal cell). In some embodiments, the cell is a mammalian cell suchas a human cell, cow cell, pig cell, horse cell, dog cell and cat cell,mouse cell, or rat cell. In some embodiments, the cell is a human cell.The cell may form part of an organ or an organism. In certainembodiments, the cell does not form part of an organ or an organism.

In another aspect, a method of inhibiting the activity of Olig2 in acell is provided. The method includes contacting the cell with acompound as provided herein (e.g. Formula (I), (II), (III), and (IV)).In some embodiments the compound binds the hinge region of thedimerization loop of Olig2. In some embodiments, the compound inhibitsdimerization of Olig2.

Compounds

Compounds described herein inhibit the activity of Olig2 within a celland may be used in the treatment of diseases or conditions whereinhibition of Olig2 activity has a beneficial effect.

In one aspect, described herein is a compound of Formula (I):

wherein:

is naphthalene or a bicyclic C₅-C₉heteroaryl, wherein

is unsubstituted or substituted by 1, 2, or 3 R₁ groups;

-   -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₉heteroaryl;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₄ and R₅ are independently H, halogen, —CN, —OH, —CF₃,        substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆alkoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₉heteroaryl;    -   R₆ is H, unsubstituted C₁-C₆alkyl, C₁-C₆haloalkyl,        —(C(R₁₄)(R₁₅))_(m)R₁₇, —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂),        —(C(R₁₄)(R₁₅))_(m)OR₁₃, —(C(R₁₄)(R₁₅))_(n)R₁₆, or —OR₂₂;    -   each R₈ is independently H or substituted or unsubstituted        C₁-C₆alkyl;    -   each R₉ is independently substituted or unsubstituted        C₁-C₆alkyl;    -   R₁₀ is H or unsubstituted C₁-C₄alkyl;    -   R₁₁ is H, substituted or unsubstituted C₁-C₆alkyl, —C(═O)R₁₉, or        —S(═O)₂R₁₉;    -   R₁₂ is H or substituted or unsubstituted C₁-C₆alkyl;    -   R₁₃ is H or substituted or unsubstituted C₁-C₆alkyl;    -   each R₁₄ and R₁₅ is each independently H, halogen, or        substituted or unsubstituted C₁-C₆alkyl;    -   R₁₆ is substituted or unsubstituted C₂-C₇heterocycloalkyl or        —C(═O)N(R₈)₂;    -   R₁₇ is —C(═O)R₂₀, —CO₂R₂₁, —C(═O)N(R₂₁)₂, or substituted or        unsubstituted C₂-C₉heteroaryl;    -   each R₁₈ is independently H, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl,        or substituted or unsubstituted C₃-C₈cycloalkyl; or    -   two R₁₈ are taken together to form a heterocycloalkyl ring;    -   R₁₉ is substituted or unsubstituted C₁-C₆alkyl;    -   R₂₀ is substituted or unsubstituted C₁-C₆alkyl;    -   each R₂₁ is independently H, or substituted or unsubstituted        C₁-C₆alkyl; or two R₂₁ are taken together to form a        heterocycloalkyl ring;    -   R₂₂ is H, or substituted or unsubstituted C₁-C₆alkyl;    -   m is 2-6; and    -   n is 1-5; or    -   a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment is a compound of Formula (I) wherein R₁₀ is H. Inanother embodiment is a compound of Formula (I) wherein R₁₀ isunsubstituted C₁-C₄alkyl. In another embodiment is a compound of Formula(I) wherein R₁₀ is —CH₃.

In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). In another embodiment is a compound ofFormula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₂ is H. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₂ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (I) whereinR₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₂ is unsubstituted C₁-C₆alkyl.In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₂ is —CH₃. In another embodiment isa compound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂)and R₁₁ is H. In another embodiment is a compound of Formula (I) whereinR₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₁ is substituted orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₁ is unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (I) whereinR₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₁ is —CH₃. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₁ is substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₁ is C₁-C₆alkyl substituted with—OH. In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₁ is —C(═O)R₁₉. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), R₁₁ is —C(═O)R₁₉ and R₁₉ is unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (I) whereinR₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), R₁₁ is —C(═O)R₁₉ and R₁₉ is —CH₃.In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₁—S(═O)₂R₁₉. In another embodimentis a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), R₁₁ is —S(═O)₂R₁₉ and R₁₉ isunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), R₁₁ is —S(═O)₂R₁₉ andR₁₉ is —CH₃. In another embodiment is a compound of Formula (I) whereinR₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and each R₁₄ and R₁₅ is eachindependently H, halogen, or unsubstituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and each R₁₄ and R₁₅ is H. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and m is 2-4. In another embodiment is acompound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) andm is 2. In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and m is 3. In another embodiment is acompound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) andm is 4. In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and m is 5. In another embodiment is acompound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) andm is 6.

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some

embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇. In another embodiment is a compound of Formula(I) wherein R₆ is —(C(R₁₄)(R₅))_(m)R₁₇ and R₁₇ is —C(═O)R₂₀. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇, R₁₇ is —C(═O)R₂₀ and R₂₀ is unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (I) whereinR₆ is —(C(R₁₄)(R₁₅))_(m)R₇ and R₁₇ is —CO₂R₂₁. In another embodiment isa compound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇, R₁₇ is—CO₂R₂₁ and R₂₁ is unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₇, R₁₇ is—CO₂R₂₁ and R₂₁ is —CH₃. In another embodiment is a compound of Formula(I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₇ and R₁₇ is —C(═O)N(R₂₁)₂. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇, R₁₇ is —C(═O)N(R₂₁)₂ and each R₂₁ isindependently H or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₇, R₁₇ is—C(═O)N(R₂₁)₂ and each R₂₁ is H. In another embodiment is a compound ofFormula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇, R₁₇ is —C(═O)N(R₂₁)₂and each R₂₁ is unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₇, R₁₇ is—C(═O)N(R₂₁)₂ and each R₂₁ is —CH₃. In another embodiment is a compoundof Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇, R₁₇ is —C(═O)N(R₂₁)₂and one R₂₁ is H and one R₂₁ is —CH₃. In another embodiment is acompound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ issubstituted or unsubstituted C₂-C₉heteroaryl. In another embodiment is acompound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ isunsubstituted C₂-C₉heteroaryl. In another embodiment is a compound ofFormula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₇ and R₁₇ is unsubstitutedpyrrole. In another embodiment is a compound of Formula (I) wherein R₆is —(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted thiophene. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted furan. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₇ and R₁₇ is unsubstituted imidazole. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted oxazole. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted isoxazole. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₇ and R₁₇ is unsubstituted pyrazole. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted thiazole. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted isothiazole. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted pyridine. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted pyrimidine. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted pyrazine. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and each R₁₄ and R₁₅ is each independently H,halogen, or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and each R₁₄and R₁₅ is H. In another embodiment is a compound of Formula (I) whereinR₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and m is 2-4. In another embodiment is acompound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and m is 2.In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and m is 3. In another embodiment is a compound ofFormula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and m is 4. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and m is 5. In another embodiment is a compound ofFormula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and m is 6.

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In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃. In another embodiment is a compound of Formula(I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is H. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is unsubstituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is —CH₃. In another embodiment is acompound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is—CH₂CH₃. In another embodiment is a compound of Formula (I) wherein R₆is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is C₁-C₆alkyl substituted with one ormore groups selected from alkyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne,C₁-C₆alkylalkyne, halo, acyl, acyloxy, —CO₂H, —CO₂-alkyl, nitro,haloalkyl, fluoroalkyl, and amino, including mono- and di-substitutedamino. In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is C₁-C₆alkyl substituted with one ormore groups selected from aryl, heteroaryl, heterocycloalkyl, —OH,alkoxy, halo, haloalkyl, and amino, including mono- and di-substitutedamino. In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is C₁-C₆alkyl substituted with one groupselected from aryl, heteroaryl, heterocycloalkyl, —OH, alkoxy, halo,haloalkyl, and amino, including mono- and di-substituted amino. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is C₁-C₆alkyl substituted with one groupselected from —OH, halo, and amino, including mono- and di-substitutedamino. In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is C₁-C₆alkyl substituted with —OH. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃ and each R₁₄ and R₁₅ is each independently H,halogen, or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and eachR₁₄ and R₁₅ is H. In another embodiment is a compound of Formula (I)wherein R₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and m is 2-4. In another embodimentis a compound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and mis 2. In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃ and m is 3. In another embodiment is a compoundof Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and m is 4. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃ and m is 5. In another embodiment is a compoundof Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and m is 6.

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In some embodiments is a compound of (I) wherein

In some embodiments is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(n)R₁₆. In another embodiment is a compound of Formula(I) wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ is substituted orunsubstituted C₂-C₇heterocycloalkyl. In another embodiment is a compoundof Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ isunsubstituted C₂-C₇heterocycloalkyl. In another embodiment is a compoundof Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ isunsubstituted piperidine. In another embodiment is a compound of Formula(I) wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ is unsubstitutedpiperazine. In another embodiment is a compound of Formula (I) whereinR₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ is unsubstituted morpholine. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ is substituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ is C₂-C₇heterocycloalkyl substituted withC₁-C₆alkyl. In another embodiment is a compound of Formula (I) whereinR₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ is substituted piperazine. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ is —C(═O)N(R₁₈)₂. In another embodiment isa compound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆, R₁₆ is—C(═O)N(R₁₈)₂ and each R₁₈ is independently H or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (I) whereinR₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆, R₁₆ is —C(═O)N(R₁₈)₂ and each R₁₈ is H. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(n)R₁₆, R₁₆ is —C(═O)N(R₁₈)₂ and each R₁₈ isunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(I) wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆, R₁₆ is —C(═O)N(R₁₈)₂ and eachR₁₈ is —CH₃. In another embodiment is a compound of Formula (I) whereinR₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆, R₁₆ is —C(═O)N(R₁₈)₂ and one R₁₈ is H andone R₁₈ is —CH₃. In another embodiment is a compound of Formula (I)wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and each R₁₄ and R₁₅ is eachindependently H, halogen, or unsubstituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(n)R₁₆ and each R₁₄ and R₁₅ is H. In another embodimentis a compound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and nis 1. In another embodiment is a compound of Formula (I) wherein R₆ R₆is —(C(R₁₄)(R₁₅))_(n)R₁₆ and n is 2. In another embodiment is a compoundof Formula (I) wherein R₆ R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and n is 3. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(n)R₁₆ and n is 4. In another embodiment is a compound ofFormula (I) wherein R₆ is R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and n is 5.

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein R₆ is —OR₂₂.In another embodiment is a compound of Formula (I) wherein R₆ is —OR₂₂and R₂₂ is H. In another embodiment is a compound of Formula (I) whereinR₆ is —OR₂₂ and R₂₂ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (I) wherein R₆ is —OR₂₂ andR₂₂ is unsubstituted C₁-C₆alkyl. In another embodiment is a compound ofFormula (I) wherein R₆ is —OR₂₂ and R₂₂ is —CH₃.

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein R₆ is H. Insome embodiments is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein R₆ isunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(I) wherein R₆ is —CH₃. In another embodiment is a compound of Formula(I) wherein R₆ is —CH₂CH₃. In another embodiment is a compound ofFormula (I) wherein R₆ is —CH(CH₃)₂. In another embodiment is a compoundof Formula (I) wherein R₆ is —CH₂CH₂CH₃. In another embodiment is acompound of Formula (I) wherein R₆ is —CH₂CH(CH₃)₂. In anotherembodiment is a compound of Formula (I) wherein R₆ is —CH₂CH₂CH₂CH₃. Inanother embodiment is a compound of Formula (I) wherein R₆ is—CH₂CH₂CH(CH₃)₂. In another embodiment is a compound of Formula (I)wherein R₆ is —CH₂CH₂CH₂CH₂CH₃. In another embodiment is a compound ofFormula (I) wherein R₆ is —CH₂CH₂CH₂CH(CH₃)₂. In another embodiment is acompound of Formula (I) wherein R₆ is —CH₂CH₂CH₂CH₂CH₂CH₃.

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In some embodiments is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein R₄ is H. Inanother embodiment is a compound of Formula (I) wherein R₄ is halogen.In another embodiment is a compound of Formula (I) wherein R₄ is —CF₃.In another embodiment is a compound of Formula (I) wherein R₄ issubstituted or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (I) wherein R₄ is unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (I) wherein R₄ is —CH₃. Inanother embodiment is a compound of Formula (I) wherein R₄ is —CH₂CH₃.In another embodiment is a compound of Formula (I) wherein R₄ is—CH(CH₃)₂. In another embodiment is a compound of Formula (I) wherein R₄is substituted or unsubstituted C₁-C₆heteroalkyl. In another embodimentis a compound of Formula (I) wherein R₄ is substituted or unsubstitutedC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(I) wherein R₄ is substituted or unsubstituted C₃-C₈cycloalkyl. Inanother embodiment is a compound of Formula (I) wherein R₄ iscyclopropyl. In another embodiment is a compound of Formula (I) whereinR₄ is substituted or unsubstituted C₆-C₁₀aryl. In another embodiment isa compound of Formula (I) wherein R₄ is substituted or unsubstitutedC₂-C₇heteroaryl.

In another embodiment is a compound of Formula (I) wherein R₅ is H. Inanother embodiment is a compound of Formula (I) wherein R₅ is halogen.In another embodiment is a compound of Formula (I) wherein R₅ is F. Inanother embodiment is a compound of Formula (I) wherein R₅ is Cl. Inanother embodiment is a compound of Formula (I) wherein R₅ is —CF₃. Inanother embodiment is a compound of Formula (I) wherein R₅ issubstituted or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (I) wherein R₅ is unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (I) wherein R₅ is —CH₃. Inanother embodiment is a compound of Formula (I) wherein R₅ is —CH₂CH₃.In another embodiment is a compound of Formula (I) wherein R₅ is—CH(CH₃)₂. In another embodiment is a compound of Formula (I) wherein R₅is substituted or unsubstituted C₁-C₆heteroalkyl. In another embodimentis a compound of Formula (I) wherein R₅ is substituted or unsubstitutedC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(I) wherein R₅ is substituted or unsubstituted C₃-C₈cycloalkyl. Inanother embodiment is a compound of Formula (I) wherein R₅ isunsubstituted C₃-C₈cycloalkyl. In another embodiment is a compound ofFormula (I) wherein R₅ is cyclopropyl. In another embodiment is acompound of Formula (I) wherein R₅ is substituted or unsubstitutedC₆-C₁₀aryl. In another embodiment is a compound of Formula (I) whereinR₅ is substituted or unsubstituted C₂-C₇heteroaryl.

In another embodiment is a compound of Formula (I) wherein

is unsubstituted naphthalene or unsubstituted bicyclic C₅-C₉heteroaryl.In another embodiment is a compound of Formula (I) wherein

is selected from:

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

In another embodiment is a compound of Formula (I) wherein

is naphthalene or bicyclic C₅-C₉heteroaryl,

is substituted by 1, 2, or 3 R₁ groups, and each R₁ is independentlyhalogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃, —SR₈,—N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈,—N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₃-C₈cycloalkyl,substituted or unsubstituted C₆-C₁₀aryl, or substituted or unsubstitutedC₂-C₉heteroaryl. In another embodiment is a compound of Formula (I)wherein

is naphthalene or bicyclic C₅-C₉heteroaryl,

is substituted by 1, 2, or 3 R₁ groups, and each R₁ is independentlyhalogen, —CN, —OH, —OCF₃, —CF₃, —S(═O)₂N(R₈)₂, —S(═O)₂R₉, —C(═O)R₉,—CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆alkoxy, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl,substituted or unsubstituted C₃-C₈cycloalkyl, substituted orunsubstituted C₆-C₁₀aryl, or substituted or unsubstitutedC₂-C₉heteroaryl. In another embodiment is a compound of Formula (I)wherein

is naphthalene or bicyclic C₅-C₉heteroaryl,

is substituted by 1, 2, or 3 R₁ groups, and each R₁ is independentlyhalogen or substituted or unsubstituted C₁-C₆alkyl.

In another embodiment is a compound of Formula (I) wherein R₂ and R₃ areeach independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl.

In another embodiment is a compound of Formula (I) wherein R₂ and R₃ areeach H.

In another embodiment is a compound of Formula (I) wherein R₂ and R₃ areeach independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl; and at least one of R₂ and R₃ is not H. Inanother embodiment is a compound of Formula (I) wherein R₂ is H, and R₃is C₁-C₄alkyl. In another embodiment is a compound of Formula (I)wherein R₂ is H, and R₃ is CH₃. In another embodiment is a compound ofFormula (I) wherein R₂ is H, and R₃ is C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (I) wherein R₂ is H, and R₃ iscyclopropyl. In another embodiment is a compound of Formula (I) whereinR₂ is H, and R₃ is cyclopentyl. In another embodiment is a compound ofFormula (I) wherein R₂ is CH₃, and R₃ is CH₃. In another embodiment is acompound of Formula (I) wherein R₂ is C₁-C₄alkyl, and R₃ is H. Inanother embodiment is a compound of Formula (I) wherein R₂ is CH₃, andR₃ is H. In another embodiment is a compound of Formula (I) wherein R₂is C₃-C₆cycloalkyl, and R₃ is H. In another embodiment is a compound ofFormula (I) wherein R₂ is cyclopropyl, and R₃ is H. In anotherembodiment is a compound of Formula (I) wherein R₂ is cyclopentyl, andR₃ is H.

In another embodiment is a compound of Formula (I) wherein R₂ and R₃ aretaken together to form a 5- or 6-membered heterocyclic ring. In anotherembodiment is a compound of Formula (I) wherein R₂ and R₃ are takentogether to form a 5-membered heterocyclic ring. In another embodimentis a compound of Formula (I) wherein R₂ and R₃ are taken together toform 6-membered heterocyclic ring.

In another aspect, described herein is a compound of Formula (II):

wherein:

-   -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted phenoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl; or two R₁ are        taken together to form a substituted or unsubstituted        heterocyclic ring or a substituted or unsubstituted carbocyclic        ring;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₄ is H, halogen, —CN, —OH, —CF₃, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   R₆ is —OR₇;    -   R₇ is H, or substituted or unsubstituted C₁-C₆alkyl;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   each R₉ is independently substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₆-C₁₀aryl; and    -   n is 0-5; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment is a compound of Formula (II) wherein R₁₀ is H. Inanother embodiment is a compound of Formula (II) wherein R₁₀ isunsubstituted C₁-C₄alkyl. In another embodiment is a compound of Formula(II) wherein R₁₀ is —CH₃.

In another embodiment is a compound of Formula (II) wherein R₇ is H. Inanother embodiment is a compound of Formula (II) wherein R₇ issubstituted or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (I) wherein R₇ is unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (II) wherein R₇ is —CH₃. Insome embodiments is a compound of Formula (II) wherein

In some embodiments is a compound of Formula (II) wherein

In some embodiments is a compound of Formula (II) wherein

In another embodiment is a compound of Formula (II) wherein R₄ is H. Inanother embodiment is a compound of Formula (II) wherein R₄ is halogen.In another embodiment is a compound of Formula (II) wherein R₄ is —CF₃.In another embodiment is a compound of Formula (II) wherein R₄ issubstituted or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (II) wherein R₄ is —CH₃. In another embodiment is acompound of Formula (II) wherein R₄ is —CH₂CH₃. In another embodiment isa compound of Formula (II) wherein R₄ is —CH(CH₃)₂. In anotherembodiment is a compound of Formula (II) wherein R₄ is substituted orunsubstituted C₁-C₆heteroalkyl. In another embodiment is a compound ofFormula (II) wherein R₄ is substituted or unsubstitutedC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(II) wherein R₄ is substituted or unsubstituted C₃-C₈cycloalkyl. Inanother embodiment is a compound of Formula (II) wherein R₄ iscyclopropyl. In another embodiment is a compound of Formula (II) whereinR₄ is substituted or unsubstituted C₆-C₁₀aryl. In another embodiment isa compound of Formula (II) wherein R₄ is substituted or unsubstitutedC₂-C₇heteroaryl.

In another embodiment is a compound of Formula (II) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(II) wherein R₂ and R₃ are each H.

In another embodiment is a compound of Formula (II) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl; and at least one of R₂ and R₃ is not H. Inanother embodiment is a compound of Formula (II) wherein R₂ is H, and R₃is C₁-C₄alkyl. In another embodiment is a compound of Formula (II)wherein R₂ is H, and R₃ is CH₃. In another embodiment is a compound ofFormula (II) wherein R₂ is H, and R₃ is C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (II) wherein R₂ is H, and R₃ iscyclopropyl. In another embodiment is a compound of Formula (II) whereinR₂ is H, and R₃ is cyclopentyl. In another embodiment is a compound ofFormula (II) wherein R₂ is CH₃, and R₃ is CH₃. In another embodiment isa compound of Formula (II) wherein R₂ is C₁-C₄alkyl, and R₃ is H. Inanother embodiment is a compound of Formula (II) wherein R₂ is CH₃, andR₃ is H. In another embodiment is a compound of Formula (II) wherein R₂is C₃-C₆cycloalkyl, and R₃ is H. In another embodiment is a compound ofFormula (II) wherein R₂ is cyclopropyl, and R₃ is H. In anotherembodiment is a compound of Formula (II) wherein R₂ is cyclopentyl, andR₃ is H.

In another embodiment is a compound of Formula (II) wherein R₂ and R₃are taken together to form a 5- or 6-membered heterocyclic ring. Inanother embodiment is a compound of Formula (II) wherein R₂ and R₃ aretaken together to form a 5-membered heterocyclic ring. In anotherembodiment is a compound of Formula (II) wherein R₂ and R₃ are takentogether to form 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (II) wherein n is 0.

In another embodiment is a compound of Formula (II) wherein each R₁ isindependently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —SR₈,—N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈,—N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₃-C₈cycloalkyl,substituted or unsubstituted C₆-C₁₀aryl, or substituted or unsubstitutedC₂-C₇heteroaryl. In another embodiment is a compound of Formula (II)wherein each R₁ is independently halogen, —CN, —OH, substituted orunsubstituted C₁-C₆alkyl, or substituted or unsubstituted C₁-C₆alkoxy.In another embodiment is a compound of Formula (II) wherein each R₁ isindependently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (II) wherein each R₁ is independently halogen, —CN, —OCF₃,—OCH₂F, —OCF₂H, substituted or unsubstituted C₁-C₆alkyl, or substitutedor unsubstituted C₁-C₆alkoxy. In another embodiment is a compound ofFormula (II) wherein each R₁ is independently halogen, —CN, —OCF₃,—OCH₂F, —OCF₂H, substituted or unsubstituted C₁-C₆alkyl, or substitutedor unsubstituted C₁-C₆alkoxy, and n is 3. In another embodiment is acompound of Formula (II) wherein each R₁ is independently halogen, —CN,—OCF₃, —OCH₂F, —OCF₂H, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆alkoxy, and n is 2. In anotherembodiment is a compound of Formula (II) wherein n is 3, and each R₁ isindependently halogen. In another embodiment is a compound of Formula(II) wherein n is 2, and each R₁ is independently halogen. In anotherembodiment is a compound of Formula (II) wherein n is 2, and each R₁ isindependently F or Cl. In another embodiment is a compound of Formula(II) wherein n is 2, and each R₁ is F. In another embodiment is acompound of Formula (II) wherein n is 2, and each R₁ is independentlyCl. In another embodiment is a compound of Formula (II) wherein n is 1,and R₁ is halogen. In another embodiment is a compound of Formula (II)wherein n is 1, and R₁ is F. In another embodiment is a compound ofFormula (II) wherein n is 1, and R₁ is Cl. In another embodiment is acompound of Formula (II) wherein n is 1, and R₁ is substituted orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(II) wherein n is 1, and R₁ is CH₃. In another embodiment is a compoundof Formula (II) wherein n is 1, and R₁ is substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (II) whereinn is 1, and R₁ is —OCH₃. In another embodiment is a compound of Formula(II) wherein n is 1, and R₁ is —OCF₃. In another embodiment is acompound of Formula (II) wherein n is 1, and R₁ is —OCF₂H.

In another aspect, described herein is a compound of Formula (III):

wherein:

-   -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₄ and R₅ are independently H, halogen, —CN, —OH, —CF₃,        substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆alkoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₉heteroaryl;    -   R₆ is H, unsubstituted C₁-C₆alkyl, —(C(R₁₄)(R₁₅))_(m)R₁₇,        —(C(R₄)(R₁₅))_(m)N(R₁₁)(R₁₂), —(C(R₁₄)(R₁₅))_(m)OR₁₃,        —(C(R₁₄)(R₁₅))_(n)R₁₆, or —OR₂₂;    -   R₇ is substituted or unsubstituted phenoxy or —C(═O)R₂₃;    -   each R₈ is independently H or substituted or unsubstituted        C₁-C₆alkyl;    -   each R₉ is independently substituted or unsubstituted        C₁-C₆alkyl;    -   R₁₀ or unsubstituted C₁-C₄alkyl;    -   R₁₁ is H, substituted or unsubstituted C₁-C₆alkyl, —C(═O)R₁₉, or        —S(═O)₂R₁₉;    -   R₁₂ is H or substituted or unsubstituted C₁-C₆alkyl;    -   R₁₃ is H or substituted or unsubstituted C₁-C₆alkyl;    -   each R₁₄ and R₁₅ is each independently H, halogen, or        substituted or unsubstituted C₁-C₆alkyl;    -   R₁₆ is substituted or unsubstituted C₂-C₇heterocycloalkyl or        —C(═O)N(R₁₈)₂;    -   R₁₇ is —C(═O)R₂₀, —CO₂R₂₁, —C(═O)N(R₂₁)₂, or substituted or        unsubstituted C₂-C₉heteroaryl;    -   each R₁₈ is independently H, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl,        or substituted or unsubstituted C₃-C₈cycloalkyl; or    -   two R₁₈ are taken together to form a heterocycloalkyl ring;    -   R₁₉ is substituted or unsubstituted C₁-C₆alkyl;    -   R₂₀ is substituted or unsubstituted C₁-C₆alkyl;    -   each R₂₁ is independently H, or substituted or unsubstituted        C₁-C₆alkyl; or two R₂₁ are taken together to form a        heterocycloalkyl ring;    -   R₂₂ is H, or substituted or unsubstituted C₁-C₆alkyl;    -   R₂₃ is substituted or unsubstituted C₆-C₁₀aryl;    -   m is 2-6;    -   n is 1-5; and    -   p is 0-4; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment is a compound of Formula (III) wherein R₇ issubstituted or unsubstituted phenoxy. In another embodiment is acompound of Formula (III) wherein R₇ is substituted phenoxy. In anotherembodiment is a compound of Formula (III) wherein R₇ is phenoxysubstituted with one or more groups selected from alkyl, cycloalkyl,aryl, heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN,alkyne, C₁-C₆alkylalkyne, halo, acyl, acyloxy, —CO₂H, —CO₂-alkyl, nitro,haloalkyl, fluoroalkyl, and amino, including mono- and di-substitutedamino. In another embodiment is a compound of Formula (III) wherein R₇is phenoxy substituted with one or more groups selected from alkyl,cycloalkyl, aryl, heteroaryl, heterocycloalkyl, —OH, alkoxy, halo,haloalkyl, and amino. In another embodiment is a compound of Formula(III) wherein R₇ is phenoxy substituted with one or more groups selectedfrom alkyl, halo, and haloalkyl. In another embodiment is a compound ofFormula (III) wherein p is 0 and R₇ is phenoxy substituted with one ormore groups selected from alkyl, halo, and haloalkyl. In anotherembodiment is a compound of Formula (III) wherein p is 1 and R₇ isphenoxy substituted with one or more groups selected from alkyl, halo,and haloalkyl. In another embodiment is a compound of Formula (III)wherein R₇ is unsubstituted phenoxy. In another embodiment is a compoundof Formula (III) wherein p is 0 and R₇ is unsubstituted phenoxy. Inanother embodiment is a compound of Formula (III) wherein p is 1 and R₇is unsubstituted phenoxy.

In another embodiment is a compound of Formula (III) wherein R₇ is—C(═O)R₂₃. In another embodiment is a compound of Formula (III) whereinR₇ is —C(═O)R₂₃ and R₂₃ is substituted or unsubstituted phenyl. Inanother embodiment is a compound of Formula (III) wherein R₇ is—C(═O)R₂₃ and R₂₃ is unsubstituted phenyl. In another embodiment is acompound of Formula (III) wherein R₇ is —C(═O)R₂₃ and R₂₃ is substitutedphenyl. In another embodiment is a compound of Formula (III) wherein R₇is —C(═O)R₂₃ and R₂₃ is phenyl substituted with one or more groupsselected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,—OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide,arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne, C₁-C₆alkylalkyne,halo, acyl, acyloxy, —CO₂H, —CO₂— alkyl, nitro, haloalkyl, fluoroalkyl,and amino, including mono- and di-substituted amino. In anotherembodiment is a compound of Formula (III) wherein R₇ is —C(═O)R₂₃ andR₂₃ is phenyl substituted with one or more groups selected from alkyl,cycloalkyl, aryl, heteroaryl, heterocycloalkyl, —OH, alkoxy, halo,haloalkyl, and amino. In another embodiment is a compound of Formula(III) wherein R₇ is —C(═O)R₂₃ and R₂₃ is phenyl substituted with one ormore groups selected from alkyl, halo, and haloalkyl.

In another embodiment is a compound of Formula (III) wherein R₁₀ is H.In another embodiment is a compound of Formula (III) wherein R₁₀ isunsubstituted C₁-C₄alkyl. In another embodiment is a compound of Formula(III) wherein R₁₀ is —CH₃.

In another embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). In another embodiment is a compound ofFormula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₂ is H.In another embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₂ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (III) whereinR₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₂ is unsubstituted C₁-C₆alkyl.In another embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₂ is —CH₃. In another embodiment isa compound of Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂)and R₁₁ is H. In another embodiment is a compound of Formula (III)wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₁ is substituted orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₁ isunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₁ is —CH₃. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₁ is substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₁ is C₁-C₆alkyl substituted with—OH. In another embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₁ is —C(═O)R₁₉. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), R₁₁ is —C(═O)R₁₉ and R₁₉ is unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (III) whereinR₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), R₁₁ is —C(═O)R₁₉ and R₁₉ is —CH₃.In another embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₁—S(═O)₂R₁₉. In another embodimentis a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), R₁₁ is —S(═O)₂R₁₉ and R₁₉ isunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), R₁₁ is —S(═O)₂R₁₉ andR₁₉ is —CH₃. In another embodiment is a compound of Formula (III)wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and each R₁₄ and R₁₅ is eachindependently H, halogen, or unsubstituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and each R₁₄ and R₁₅ is H. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and m is 2-4. In another embodiment is acompound of Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂)and m is 2. In another embodiment is a compound of Formula (III) whereinR₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and m is 3. In another embodiment isa compound of Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂)and m is 4. In another embodiment is a compound of Formula (III) whereinR₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and m is 5. In another embodiment isa compound of Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂)and m is 6.

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇. In another embodiment is a compound of Formula(III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is —C(═O)R₂₀. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇, R₁₇ is —C(═O)R₂₀ and R₂₀ is unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (III) whereinR₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is —CO₂R₂₁. In another embodiment isa compound of Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₇, R₁₇ is—CO₂R₂₁ and R₂₁ is unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇, R₁₇ is—CO₂R₂₁ and R₂₁ is —CH₃. In another embodiment is a compound of Formula(III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is —C(═O)N(R₂₁)₂. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇, R₁₇ is —C(═O)N(R₂₁)₂ and each R₂₁ isindependently H or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇, R₁₇ is—C(═O)N(R₂₁)₂ and each R₂₁ is H. In another embodiment is a compound ofFormula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇, R₁₇ is —C(═O)N(R₂₁)₂and each R₂₁ is unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇, R₁₇ is—C(═O)N(R₂₁)₂ and each R₂₁ is —CH₃. In another embodiment is a compoundof Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇, R₁₇ is—C(═O)N(R₂₁)₂ and one R₂₁ is H and one R₂₁ is —CH₃. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is substituted or unsubstitutedC₂-C₉heteroaryl. In another embodiment is a compound of Formula (III)wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstitutedC₂-C₉heteroaryl. In another embodiment is a compound of Formula (III)wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted pyrrole. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted thiophene. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted furan. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted imidazole. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted oxazole. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted isoxazole. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted pyrazole. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted thiazole. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted isothiazole. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted pyridine. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted pyrimidine. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and R₁₇ is unsubstituted pyrazine. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and each R₁₄ and R₁₅ is each independently H,halogen, or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and eachR₁₄ and R₁₅ is H. In another embodiment is a compound of Formula (III)wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and m is 2-4. In another embodimentis a compound of Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and mis 2. In another embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and m is 3. In another embodiment is a compound ofFormula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and m is 4. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₁₇ and m is 5. In another embodiment is a compound ofFormula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₁₇ and m is 6.

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In another embodiment is a compound of Formula (III) wherein

In another embodiment is a compound of Formula (III) wherein

In another embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃. In another embodiment is a compound of Formula(III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is H. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is unsubstituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is —CH₃. In another embodiment is acompound of Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃is —CH₂CH₃. In another embodiment is a compound of Formula (III) whereinR₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is C₁-C₆alkyl substituted with one ormore groups selected from alkyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne,C₁-C₆alkylalkyne, halo, acyl, acyloxy, —CO₂H, —CO₂-alkyl, nitro,haloalkyl, fluoroalkyl, and amino, including mono- and di-substitutedamino. In another embodiment is a compound of Formula (III) wherein R₆is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is C₁-C₆alkyl substituted with one ormore groups selected from aryl, heteroaryl, heterocycloalkyl, —OH,alkoxy, halo, haloalkyl, and amino, including mono- and di-substitutedamino. In another embodiment is a compound of Formula (III) wherein R₆is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is C₁-C₆alkyl substituted with onegroup selected from aryl, heteroaryl, heterocycloalkyl, —OH, alkoxy,halo, haloalkyl, and amino, including mono- and di-substituted amino. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is C₁-C₆alkyl substituted with one groupselected from —OH, halo, and amino, including mono- and di-substitutedamino. In another embodiment is a compound of Formula (III) wherein R₆is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and R₁₃ is C₁-C₆alkyl substituted with —OH. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(C(R₄)(R₁₅))_(m)OR₁₃ and each R₁₄ and R₁₅ is each independently H,halogen, or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and eachR₁₄ and R₁₅ is H. In another embodiment is a compound of Formula (III)wherein R₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and m is 2-4. In another embodimentis a compound of Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃ andm is 2. In another embodiment is a compound of Formula (III) wherein R₆is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and m is 3. In another embodiment is acompound of Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and m is4. In another embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)OR₁₃ and m is 5. In another embodiment is a compoundof Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)OR₁₃ and m is 6.

In some embodiments is a compound of Formula (III) wherein

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In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In another embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(n)R₁₆. In another embodiment is a compound of Formula(III) wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ is substituted orunsubstituted C₂-C₇heterocycloalkyl. In another embodiment is a compoundof Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ isunsubstituted C₂-C₇heterocycloalkyl. In another embodiment is a compoundof Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ isunsubstituted piperidine. In another embodiment is a compound of Formula(III) wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ is unsubstitutedpiperazine. In another embodiment is a compound of Formula (III) whereinR₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ is unsubstituted morpholine. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ is substituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ is C₂-C₇heterocycloalkyl substituted withC₁-C₆alkyl. In another embodiment is a compound of Formula (III) whereinR₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ is substituted piperazine. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(n)R₁₆ and R₁₆ is —C(═O)N(R₁₈)₂. In another embodiment isa compound of Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆, R₁₆ is—C(═O)N(R₁₈)₂ and each R₁₈ is independently H or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (III) whereinR₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆, R₁₆ is —C(═O)N(R₁₈)₂ and each R₁₈ is H. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(n)R₁₆, R₁₆ is —C(═O)N(R₁₈)₂ and each R₁₈ isunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(III) wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆, R₁₆ is —C(═O)N(R₁₈)₂ and eachR₁₈ is —CH₃. In another embodiment is a compound of Formula (III)wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆, R₁₆ is —C(═O)N(R₁₈)₂ and one R₁₈ isH and one R₁₈ is —CH₃. In another embodiment is a compound of Formula(III) wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and each R₁₄ and R₁₅ is eachindependently H, halogen, or unsubstituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(n)R₁₆ and each R₁₄ and R₁₅ is H. In another embodimentis a compound of Formula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and nis 1. In another embodiment is a compound of Formula (III) wherein R₆ R₆is —(C(R₁₄)(R₁₅))_(n)R₁₆ and n is 2. In another embodiment is a compoundof Formula (III) wherein R₆ R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and n is 3. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(n)R₁₆ and n is 4. In another embodiment is a compound ofFormula (III) wherein R₆ is R₆ is —(C(R₁₄)(R₁₅))_(n)R₁₆ and n is 5.

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In another embodiment is a compound of Formula (III) wherein R₆ is—OR₂₂. In another embodiment is a compound of Formula (III) wherein R₆is —OR₂₂ and R₂₂ is H. In another embodiment is a compound of Formula(III) wherein R₆ is —OR₂₂ and R₂₂ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (III) whereinR₆ is —OR₂₂ and R₂₂ is unsubstituted C₁-C₆alkyl. In another embodimentis a compound of Formula (III) wherein R₆ is —OR₂₂ and R₂₂ is —CH₃.

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In another embodiment is a compound of Formula (III) wherein R₆ is H. Insome embodiments is a compound of Formula (III) wherein

In another embodiment is a compound of Formula (III) wherein R₆ isunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(III) wherein R₆ is —CH₃. In another embodiment is a compound of Formula(III) wherein R₆ is —CH₂CH₃. In another embodiment is a compound ofFormula (III) wherein R₆ is —CH(CH₃)₂. In another embodiment is acompound of Formula (III) wherein R₆ is —CH₂CH₂CH₃. In anotherembodiment is a compound of Formula (III) wherein R₆ is —CH₂CH(CH₃)₂. Inanother embodiment is a compound of Formula (III) wherein R₆ is—CH₂CH₂CH₂CH₃. In another embodiment is a compound of Formula (III)wherein R₆ is —CH₂CH₂CH(CH₃)₂. In another embodiment is a compound ofFormula (III) wherein R₆ is —CH₂CH₂CH₂CH₂CH₃. In another embodiment is acompound of Formula (III) wherein R₆ is —CH₂CH₂CH₂CH(CH₃)₂. In anotherembodiment is a compound of Formula (III) wherein R₆ is—CH₂CH₂CH₂CH₂CH₂CH₃.

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In some embodiments is a compound of Formula (III) wherein

In another embodiment is a compound of Formula (III) wherein R₄ is H. Inanother embodiment is a compound of Formula (III) wherein R₄ is halogen.In another embodiment is a compound of Formula (III) wherein R₄ is —CF₃.In another embodiment is a compound of Formula (III) wherein R₄ issubstituted or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (III) wherein R₄ is unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (III) wherein R₄ is —CH₃. Inanother embodiment is a compound of Formula (III) wherein R₄ is —CH₂CH₃.In another embodiment is a compound of Formula (III) wherein R₄ is—CH(CH₃)₂. In another embodiment is a compound of Formula (III) whereinR₄ is substituted or unsubstituted C₁-C₆heteroalkyl. In anotherembodiment is a compound of Formula (III) wherein R₄ is substituted orunsubstituted C₂-C₇heterocycloalkyl. In another embodiment is a compoundof Formula (III) wherein R₄ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (III)wherein R₄ is cyclopropyl. In another embodiment is a compound ofFormula (III) wherein R₄ is substituted or unsubstituted C₆-C₁₀aryl. Inanother embodiment is a compound of Formula (III) wherein R₄ issubstituted or unsubstituted C₂-C₇heteroaryl.

In another embodiment is a compound of Formula (III) wherein R₅ is H. Inanother embodiment is a compound of Formula (III) wherein R₅ is halogen.In another embodiment is a compound of Formula (III) wherein R₅ is F. Inanother embodiment is a compound of Formula (III) wherein R₅ is —CF₃. Inanother embodiment is a compound of Formula (III) wherein R₅ issubstituted or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (III) wherein R₅ is unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (III) wherein R₅ is —CH₃. Inanother embodiment is a compound of Formula (III) wherein R₅ is —CH₂CH₃.In another embodiment is a compound of Formula (III) wherein R₅ is—CH(CH₃)₂. In another embodiment is a compound of Formula (III) whereinR₅ is substituted or unsubstituted C₁-C₆heteroalkyl. In anotherembodiment is a compound of Formula (III) wherein R₅ is substituted orunsubstituted C₂-C₇heterocycloalkyl. In another embodiment is a compoundof Formula (III) wherein R₅ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (III)wherein R₅ is unsubstituted C₃-C₈cycloalkyl. In another embodiment is acompound of Formula (III) wherein R₅ is cyclopropyl. In anotherembodiment is a compound of Formula (III) wherein R₅ is substituted orunsubstituted C₆-C₁₀aryl. In another embodiment is a compound of Formula(III) wherein R₅ is substituted or unsubstituted C₂-C₇heteroaryl.

In another embodiment is a compound of Formula (III) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl.

In another embodiment is a compound of Formula (III) wherein R₂ and R₃are each H.

In another embodiment is a compound of Formula (III) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl; and at least one of R₂ and R₃ is not H. Inanother embodiment is a compound of Formula (III) wherein R₂ is H, andR₃ is C₁-C₄alkyl. In another embodiment is a compound of Formula (III)wherein R₂ is H, and R₃ is CH₃. In another embodiment is a compound ofFormula (III) wherein R₂ is H, and R₃ is C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (III) wherein R₂ is H, and R₃ iscyclopropyl. In another embodiment is a compound of Formula (III)wherein R₂ is H, and R₃ is cyclopentyl. In another embodiment is acompound of Formula (III) wherein R₂ is CH₃, and R₃ is CH₃. In anotherembodiment is a compound of Formula (III) wherein R₂ is C₁-C₄alkyl, andR₃ is H. In another embodiment is a compound of Formula (III) wherein R₂is CH₃, and R₃ is H. In another embodiment is a compound of Formula(III) wherein R₂ is C₃-C₆cycloalkyl, and R₃ is H. In another embodimentis a compound of Formula (III) wherein R₂ is cyclopropyl, and R₃ is H.In another embodiment is a compound of Formula (III) wherein R₂ iscyclopentyl, and R₃ is H.

In another embodiment is a compound of Formula (III) wherein R₂ and R₃are taken together to form a 5- or 6-membered heterocyclic ring. Inanother embodiment is a compound of Formula (III) wherein R₂ and R₃ aretaken together to form a 5-membered heterocyclic ring. In anotherembodiment is a compound of Formula (III) wherein R₂ and R₃ are takentogether to form 6-membered heterocyclic ring.

In another aspect, described herein is a compound of Formula (IV):

wherein:

-   -   each R₁ is independently halogen, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,        unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆alkoxy,        unsubstituted phenyl, or unsubstituted C₂-C₉heteroaryl;    -   R₆ is H, unsubstituted C₁-C₆alkyl, —(CH₂)_(m)N(R₁₁)(R₁₂), or        —(CH₂)_(m)OR₁₃;    -   R₉ is unsubstituted C₁-C₆alkyl;    -   R₁₀ or unsubstituted C₁-C₄alkyl;    -   R₁₁ is H, unsubstituted C₁-C₆alkyl, —C(═O)R₉, or —S(═O)₂R₉;    -   R₁₂ is H or unsubstituted C₁-C₆alkyl;    -   R₁₃ is H or unsubstituted C₁-C₆alkyl;    -   m is 2-4; and    -   p is 1-3; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment is a compound of Formula (IV) wherein R₁₀ is H. Inanother embodiment is a compound of Formula (IV) wherein R₁₀ isunsubstituted C₁-C₄alkyl. In another embodiment is a compound of Formula(IV) wherein R₁₀ is —CH₃.

In another embodiment is a compound of Formula (IV) wherein R₆ is H. Insome embodiments is a compound of Formula (IV) wherein R₁₀ is

In another embodiment is a compound of Formula (IV) wherein R₆ isunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IV) wherein R₆ is —CH₃. In another embodiment is a compound of Formula(IV) wherein R₆ is —CH₂CH₃. In another embodiment is a compound ofFormula (IV) wherein R₆ is —CH(CH₃)₂. In another embodiment is acompound of Formula (IV) wherein R₆ is —CH₂CH₂CH₃. In another embodimentis a compound of Formula (IV) wherein R₆ is —CH₂CH(CH₃)₂. In anotherembodiment is a compound of Formula (IV) wherein R₆ is —CH₂CH₂CH₂CH₃. Inanother embodiment is a compound of Formula (IV) wherein R₆ is—CH₂CH₂CH(CH₃)₂. In another embodiment is a compound of Formula (IV)wherein R₆ is —CH₂CH₂CH₂CH₂CH₃. In another embodiment is a compound ofFormula (IV) wherein R₆ is —CH₂CH₂CH₂CH(CH₃)₂. In another embodiment isa compound of Formula (IV) wherein R₆ is —CH₂CH₂CH₂CH₂CH₂CH₃.

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In another embodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂). In another embodiment is a compound of Formula(IV) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂) and R₁₂ is H. In anotherembodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂) and R₁₂ is unsubstituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂) and R₁₂ is —CH₃. In another embodiment is acompound of Formula (IV) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂) and R₁₁ isH. In another embodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂) and R₁₁ is unsubstituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂) and R₁₁ is —CH₃. In another embodiment is acompound of Formula (IV) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂) and R₁₁ is—C(═O)R₁₉. In another embodiment is a compound of Formula (IV) whereinR₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), R₁₁ is —C(═O)R₁₉ and R₁₉ is —CH₃. Inanother embodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂) and R₁₁—S(═O)₂R₁₉. In another embodiment is acompound of Formula (IV) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), R₁₁ is—S(═O)₂R₁₉ and R₁₉ is —CH₃. In another embodiment is a compound ofFormula (IV) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂) and m is 2. In anotherembodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂) and m is 3. In another embodiment is a compound ofFormula (IV) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂) and m is 4.

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In another embodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)OR₃. In another embodiment is a compound of Formula (IV)wherein R₆ is —(CH₂)_(m)OR₁₃ and R₁₃ is H. In another embodiment is acompound of Formula (IV) wherein R₆ is —(CH₂)_(m)OR₁₃ and R₁₃ isunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IV) wherein R₆ is —(CH₂)_(m)OR₁₃ and R₁₃ is —CH₃. In another embodimentis a compound of Formula (IV) wherein R₆ is —(CH₂)_(m)OR₁₃ and R₁₃ is—CH₂CH₃. In another embodiment is a compound of Formula (IV) wherein R₆is —(CH₂)_(m)OR₁₃ and m is 2. In another embodiment is a compound ofFormula (IV) wherein R₆ is —(CH₂)_(m)OR₁₃ and m is 3. In anotherembodiment is a compound of Formula (IV) wherein R₆ is —(CH₂)_(m)OR₁₃and m is 4.

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In some embodiments is a compound of Formula (IV) wherein

In another embodiment is a compound of Formula (IV) wherein each R₁ isindependently halogen, —OCF₃, —CF₃, unsubstituted C₁-C₆alkyl,unsubstituted C₁-C₆alkoxy, unsubstituted phenyl, or unsubstitutedC₂-C₉heteroaryl. In another embodiment is a compound of Formula (IV)wherein each R₁ is independently halogen, —OCF₃, —CF₃, unsubstitutedC₁-C₆alkyl, unsubstituted C₁-C₆alkoxy, or unsubstituted phenyl. Inanother embodiment is a compound of Formula (IV) wherein each R₁ isindependently halogen, —OCF₃, —CF₃, unsubstituted C₁-C₆alkyl,unsubstituted C₁-C₆alkoxy, or unsubstituted phenyl, and p is 3. Inanother embodiment is a compound of Formula (IV) wherein each R₁ isindependently halogen, —OCF₃, —CF₃, unsubstituted C₁-C₆alkyl,unsubstituted C₁-C₆alkoxy, or unsubstituted phenyl, and p is 2. Inanother embodiment is a compound of Formula (IV) wherein R₁ is halogen,—OCF₃, —CF₃, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆alkoxy, orunsubstituted phenyl, and p is 1. In another embodiment is a compound ofFormula (IV) wherein p is 3, and each R₁ is independently halogen. Inanother embodiment is a compound of Formula (IV) wherein p is 2, andeach R₁ is independently halogen. In another embodiment is a compound ofFormula (IV) wherein p is 2, and each R₁ is independently F or Cl. Inanother embodiment is a compound of Formula (IV) wherein p is 2, andeach R₁ is F. In another embodiment is a compound of Formula (IV)wherein p is 2, and each R₁ is independently Cl. In another embodimentis a compound of Formula (IV) wherein p is 1, and R₁ is halogen. Inanother embodiment is a compound of Formula (IV) wherein p is 1, and R₁is F. In another embodiment is a compound of Formula (IV) wherein p is1, and R₁ is Cl. In another embodiment is a compound of Formula (IV)wherein p is 1, and R₁ is unsubstituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IV) wherein p is 1, and R₁ is CH₃.In another embodiment is a compound of Formula (IV) wherein p is 1, andR₁ is unsubstituted C₁-C₆alkoxy. In another embodiment is a compound ofFormula (IV) wherein p is 1, and R₁ is —OCH(CH₃)₂. In another embodimentis a compound of Formula (IV) wherein p is 1, and R₁ is —OCH₃. Inanother embodiment is a compound of Formula (IV) wherein p is 1, and R₁is —OCF₃. In another embodiment is a compound of Formula (IV) wherein pis 1, and R₁ is unsubstituted phenyl.

In another embodiment is a compound selected from:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment is a compound selected from:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment is a compound selected from:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment is a compound having the structure:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment is a compound having the structure:

or a solvate or prodrug thereof.

In another embodiment is a compound selected from:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment is a compound selected from:

pharmaceutically acceptable salt, solvate, or prodrug thereof.

Deuterium (D or ²H) is a stable, non-radioactive isotope of hydrogen andhas an atomic weight of 2.0144. Hydrogen naturally occurs as a mixtureof the isotopes ¹H (hydrogen or protium), D (²H or deuterium), and T (³Hor tritium). The natural abundance of deuterium is 0.015%. Generally, inchemical compounds with an H atom, the H atom actually represents amixture of H and D, with about 0.015% being D. In some embodiments,deuterium-enriched compounds described herein are achieved by eitherexchanging protons with deuterium or via starting materials and/orintermediates enriched with deuterium.

Any combination of the groups described above for the various variablesis contemplated herein.

Throughout the specification, groups and substituents thereof can bechosen to provide stable moieties and compounds.

Further Forms of Compounds

The compounds described herein may in some cases exist as diastereomers,enantiomers, or other stereoisomeric forms. The compounds presentedherein include all diastereomeric, enantiomeric, and epimeric forms aswell as the appropriate mixtures thereof. Separation of stereoisomersmay be performed by chromatography or by the forming diastereomeric andseparation by recrystallization, or chromatography, or any combinationthereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers,Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, hereinincorporated by reference for this disclosure). Stereoisomers may alsobe obtained by stereoselective synthesis.

In some situations, compounds may exist as tautomers. All tautomers areincluded within the formulas described herein.

The methods and compositions described herein include the use ofamorphous forms as well as crystalline forms (also known as polymorphs).The compounds described herein may be in the form of pharmaceuticallyacceptable salts. As well, active metabolites of these compounds havingthe same type of activity are included in the scope of the presentdisclosure. In addition, the compounds described herein can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

In some embodiments, compounds described herein may be prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. An example, withoutlimitation, of a prodrug would be a compound described herein, which isadministered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the compound. Incertain embodiments, a prodrug is enzymatically metabolized by one ormore steps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound.

To produce a prodrug, a pharmaceutically active compound is modifiedsuch that the active compound will be regenerated upon in vivoadministration. The prodrug can be designed to alter the metabolicstability or the transport characteristics of a drug, to mask sideeffects or toxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. In some embodiments, by virtueof knowledge of pharmacodynamic processes and drug metabolism in vivo,once a pharmaceutically active compound is determined, prodrugs of thecompound are designed. (see, for example, Nogrady (1985) MedicinalChemistry A Biochemical Approach, Oxford University Press, New York,pages 388-392; Silverman (1992), The Organic Chemistry of Drug Designand Drug Action, Academic Press, Inc., San Diego, pages 352-401,Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters,Vol. 4, p. 1985; Rooseboom et al., Pharmacological Reviews, 56:53-102,2004; Miller et al., J. Med. Chem. Vol. 46, no. 24, 5097-5116, 2003;Aesop Cho, “Recent Advances in Oral Prodrug Discovery”, Annual Reportsin Medicinal Chemistry, Vol. 41, 395-407, 2006).

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound of Formula (I), (II), (III),or (IV) as set forth herein are included within the scope of the claims.In some cases, some of the herein-described compounds may be a prodrugfor another derivative or active compound.

Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. Prodrugs may be designed as reversible drugderivatives, for use as modifiers to enhance drug transport tosite-specific tissues. In some embodiments, the design of a prodrugincreases the effective water solubility. See, e.g., Fedorak et al., Am.J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol,106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992);J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J.Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J.Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs asNovel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; andEdward B. Roche, Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, all incorporatedherein for such disclosure).

Sites on the aromatic ring portion of compounds described herein can besusceptible to various metabolic reactions, therefore incorporation ofappropriate substituents on the aromatic ring structures, such as, byway of example only, halogens can reduce, minimize or eliminate thismetabolic pathway.

The compounds described herein may be labeled isotopically (e.g. with aradioisotope) or by other means, including, but not limited to, the useof chromophores or fluorescent moieties, bioluminescent labels,photoactivatable or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, suchas, for example, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl,respectively. Certain isotopically-labeled compounds described herein,for example those into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Further, substitution with isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, such as, for example, increased in vivo half-lifeor reduced dosage requirements.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid, such as, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid,and the like; or with an organic acid, such as, for example, aceticacid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaricacid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, toluenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, butyric acid, phenylacetic acid,phenylbutyric acid, valproic acid, and the like; (2) salts formed whenan acidic proton present in the parent compound is replaced by a metalion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), analkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. Insome cases, compounds described herein may coordinate with an organicbase, such as, but not limited to, ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine,tris(hydroxymethyl)methylamine. In other cases, compounds describedherein may form salts with amino acids such as, but not limited to,arginine, lysine, and the like. Acceptable inorganic bases used to formsalts with compounds that include an acidic proton, include, but are notlimited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. Solvates of compounds described herein can beconveniently prepared or formed during the processes described herein.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

In some embodiments, compounds described herein, such as compounds ofFormula (I), (II), (III), or (IV), are in various forms, including butnot limited to, amorphous forms, milled forms and nano-particulateforms. In addition, compounds described herein include crystallineforms, also known as polymorphs. Polymorphs include the differentcrystal packing arrangements of the same elemental composition of acompound. Polymorphs usually have different X-ray diffraction patterns,melting points, density, hardness, crystal shape, optical properties,stability, and solubility. Various factors such as the recrystallizationsolvent, rate of crystallization, and storage temperature may cause asingle crystal form to dominate.

The screening and characterization of the pharmaceutically acceptablesalts, polymorphs and/or solvates may be accomplished using a variety oftechniques including, but not limited to, thermal analysis, x-raydiffraction, spectroscopy, vapor sorption, and microscopy. Thermalanalysis methods address thermo chemical degradation or thermo physicalprocesses including, but not limited to, polymorphic transitions, andsuch methods are used to analyze the relationships between polymorphicforms, determine weight loss, to find the glass transition temperature,or for excipient compatibility studies. Such methods include, but arenot limited to, Differential Scanning Calorimetry (DSC), ModulatedDifferential Scanning Calorimetry (MDCS), Thermogravimetric analysis(TGA), and Thermogravi-metric and Infrared analysis (TG/IR). X-raydiffraction methods include, but are not limited to, single crystal andpowder diffractometers and synchrotron sources. The variousspectroscopic techniques used include, but are not limited to, Raman,FTIR, UV-VIS, and NMR (liquid and solid state). The various microscopytechniques include, but are not limited to, polarized light microscopy,Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis(EDX), Environmental Scanning Electron Microscopy with EDX (in gas orwater vapor atmosphere), IR microscopy, and Raman microscopy.

Throughout the specification, groups and substituents thereof can bechosen to provide stable moieties and compounds.

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley andSons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, ADVANCED ORGANICCHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANICCHEMISTRY 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Greene andWuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).

Certain Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood to which the claimedsubject matter belongs. In the event that there are a plurality ofdefinitions for terms herein, those in this section prevail. Allpatents, patent applications, publications and published nucleotide andamino acid sequences (e.g., sequences available in GenBank or otherdatabases) referred to herein are incorporated by reference. Wherereference is made to a URL or other such identifier or address, it isunderstood that such identifiers can change and particular informationon the internet can come and go, but equivalent information can be foundby searching the internet. Reference thereto evidences the availabilityand public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Definition of standard chemistry terms may be found in reference works,including but not limited to, Carey and Sundberg “ADVANCED ORGANICCHEMISTRY 4TH ED.” Vols. A (2000) and B (2001), Plenum Press, New York.Unless otherwise indicated, conventional methods of mass spectroscopy,NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniquesand pharmacology.

Unless specific definitions are provided, the nomenclature employed inconnection with, and the laboratory procedures and techniques of,analytical chemistry, synthetic organic chemistry, and medicinal andpharmaceutical chemistry described herein are those recognized in thefield. Standard techniques can be used for chemical syntheses, chemicalanalyses, pharmaceutical preparation, formulation, and delivery, andtreatment of patients. Standard techniques can be used for recombinantDNA, oligonucleotide synthesis, and tissue culture and transformation(e.g., electroporation, lipofection). Reactions and purificationtechniques can be performed e.g., using kits of manufacturer'sspecifications or as commonly accomplished in the art or as describedherein. The foregoing techniques and procedures can be generallyperformed of conventional methods and as described in various generaland more specific references that are cited and discussed throughout thepresent specification.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the methods, compounds, compositions describedherein.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). C₁-C_(x)refers to the number of carbon atoms that make up the moiety to which itdesignates (excluding optional substituents).

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroups may or may not include units of unsaturation. The alkyl moietymay be a “saturated alkyl” group, which means that it does not containany units of unsaturation (i.e. a carbon-carbon double bond or acarbon-carbon triple bond). The alkyl group may also be an “unsaturatedalkyl” moiety, which means that it contains at least one unit ofunsaturation. The alkyl moiety, whether saturated or unsaturated, may bebranched, straight chain, or cyclic.

The “alkyl” group may have 1 to 12 carbon atoms (whenever it appearsherein, a numerical range such as “1 to 6” refers to each integer in thegiven range; e.g., “1 to 6 carbon atoms” means that the alkyl group mayconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 6 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group of the compounds described herein may bedesignated as “C₁-C₆ alkyl” or similar designations. By way of exampleonly, “C₁-C₆ alkyl” indicates that there are one to six carbon atoms inthe alkyl chain, i.e., the alkyl chain is selected from the groupconsisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl(allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl. Alkyl groups can be substituted or unsubstituted.Depending on the structure, an alkyl group can be a monoradical or adiradical (i.e., an alkylene group).

An “alkoxy” refers to a “—O-alkyl” group, where alkyl is as definedherein.

The term “alkenyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a double bond that is not part of anaromatic group. That is, an alkenyl group begins with the atoms—C(R)═CR₂, wherein R refers to the remaining portions of the alkenylgroup, which may be the same or different. Non-limiting examples of analkenyl group include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃, —CH═C(CH₃)₂ and—C(CH₃)═CHCH₃. The alkenyl moiety may be branched, straight chain, orcyclic (in which case, it would also be known as a “cycloalkenyl”group). Alkenyl groups may have 2 to 6 carbons. Alkenyl groups can besubstituted or unsubstituted. Depending on the structure, an alkenylgroup can be a monoradical or a diradical (i.e., an alkenylene group).

The term “alkynyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a triple bond. That is, an alkynylgroup begins with the atoms —C≡C—R, wherein R refers to the remainingportions of the alkynyl group. Non-limiting examples of an alkynyl groupinclude —C≡CH, —C≡CCH₃, —C≡CCH₂CH₃ and —C≡CCH₂CH₂CH₃. The “R” portion ofthe alkynyl moiety may be branched, straight chain, or cyclic. Analkynyl group can have 2 to 6 carbons. Alkynyl groups can be substitutedor unsubstituted. Depending on the structure, an alkynyl group can be amonoradical or a diradical (i.e., an alkynylene group).

“Amino” refers to a —NH₂ group.

The term “alkylamine” or “alkylamino” refers to the —N(alkyl)_(x)H_(y)group, where alkyl is as defined herein and x and y are selected fromthe group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, takentogether with the nitrogen to which they are attached, can optionallyform a cyclic ring system. “Dialkylamino” refers to a —N(alkyl)₂ group,where alkyl is as defined herein.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2π electrons, where n is an integer.Aromatic rings can be formed from five, six, seven, eight, nine, or morethan nine atoms. Aromatics can be optionally substituted. The term“aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) andheteroaryl groups (e.g., pyridinyl, quinolinyl).

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings can be formedby five, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups can be optionally substituted. Examples of aryl groups include,but are not limited to phenyl, and naphthalenyl. Depending on thestructure, an aryl group can be a monoradical or a diradical (i.e., anarylene group).

The term “carbocyclic ring” refers to a ring wherein each of the atomsforming the ring is a carbon atom. The carbocyclic ring may be aryl orcycloalkyl.

“Carboxy” refers to —CO₂H. In some embodiments, carboxy moieties may bereplaced with a “carboxylic acid bioisostere”, which refers to afunctional group or moiety that exhibits similar physical and/orchemical properties as a carboxylic acid moiety. A carboxylic acidbioisostere has similar biological properties to that of a carboxylicacid group. A compound with a carboxylic acid moiety can have thecarboxylic acid moiety exchanged with a carboxylic acid bioisostere andhave similar physical and/or biological properties when compared to thecarboxylic acid-containing compound. For example, in one embodiment, acarboxylic acid bioisostere would ionize at physiological pH to roughlythe same extent as a carboxylic acid group. Examples of bioisosteres ofa carboxylic acid include, but are not limited to,

and the like.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. Cycloalkyls may be saturated, or partiallyunsaturated. Cycloalkyls may be fused with an aromatic ring (in whichcase the cycloalkyl is bonded through a non-aromatic ring carbon atom).Cycloalkyl groups include groups having from 3 to 10 ring atoms.Illustrative examples of cycloalkyl groups include, but are not limitedto, the following moieties:

and the like.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. Polycyclic heteroarylgroups may be fused or non-fused. Illustrative examples of heteroarylgroups include the following moieties:

and the like.

A “heterocycloalkyl” group or “heteroalicyclic” group refers to acycloalkyl group, wherein at least one skeletal ring atom is aheteroatom selected from nitrogen, oxygen and sulfur. The radicals maybe fused with an aryl or heteroaryl. Illustrative examples ofheterocycloalkyl groups, also referred to as non-aromatic heterocycles,include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Unless otherwise noted,heterocycloalkyls have from 2 to 10 carbons in the ring. It isunderstood that when referring to the number of carbon atoms in aheterocycloalkyl, the number of carbon atoms in the heterocycloalkyl isnot the same as the total number of atoms (including the heteroatoms)that make up the heterocycloalkyl (i.e. skeletal atoms of theheterocycloalkyl ring).

The term “heterocyclic ring” refers to a ring wherein at least oneskeletal ring atom is a heteroatom selected from nitrogen, oxygen andsulfur. The heterocyclic ring may be heteroaryl or heterocycloalkyl.

The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromoand iodo.

The term “haloalkyl” refers to an alkyl group that is substituted withone or more halogens. The halogens may the same or they may bedifferent. Non-limiting examples of haloalkyls include —CH₂Cl, —CF₃,—CHF₂, —CH₂CF₃, —CF₂CF₃, —CF(CH₃)₃, and the like.

The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxygroups, respectively, that are substituted with one or more fluorineatoms. Non-limiting examples of fluoroalkyls include —CF₃, —CHF₂, —CH₂F,—CH₂CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CF(CH₃)₃, and the like. Non-limitingexamples of fluoroalkoxy groups, include —OCF₃, —OCHF₂, —OCH₂F,—OCH₂CF₃, —OCF₂CF₃, —OCF₂CF₂CF₃, —OCF(CH₃)₂, and the like.

The term “heteroalkyl” refers to an alkyl radical where one or moreskeletal chain atoms is selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof.The heteroatom(s) may be placed at any interior position of theheteroalkyl group. Examples include, but are not limited to, —CH₂—O—CH₃,—CH₂—CH₂—O—CH₃, —CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH₂—NH—OCH₃, —CH₂—O—Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. In addition, up to twoheteroatoms may be consecutive, such as, by way of example, —CH₂—NH—OCH₃and —CH₂—O—Si(CH₃)₃. Excluding the number of heteroatoms, a“heteroalkyl” may have from 1 to 6 carbon atoms.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from among fromalkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon), and heterocycloalkyl.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne,C₁-C₆alkylalkyne, halo, acyl, acyloxy, —CO₂H, —CO₂-alkyl, nitro,haloalkyl, fluoroalkyl, and amino, including mono- and di-substitutedamino groups (e.g. —NH₂, —NHR, —N(R)₂), and the protected derivativesthereof. By way of example, an optional substituents may be L^(s)R^(s),wherein each L^(s) is independently selected from a bond, —O—, —C(═O)—,—S—, —S(═O)—, —S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, —S(═O)₂NH—,—NHS(═O)₂—, —OC(O)NH—, —NHC(O)O—, —(C₁-C₆alkyl)-, or —(C₂-C₆alkenyl)-;and each R^(s) is independently selected from among H, (C₁-C₆alkyl),(C₃-C₈cycloalkyl), aryl, heteroaryl, heterocycloalkyl, andC₁-C₆heteroalkyl. The protecting groups that may form the protectivederivatives of the above substituents are found in sources such asGreene and Wuts, above.

The methods and formulations described herein include the use ofcrystalline forms (also known as polymorphs), or pharmaceuticallyacceptable salts of compounds having the structure of Formula (I), (II),(III), or (IV), as well as active metabolites of these compounds havingthe same type of activity. In some situations, compounds may exist astautomers. All tautomers are included within the scope of the compoundspresented herein. In addition, the compounds described herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

The terms “kit” and “article of manufacture” are used as synonyms.

The term “subject” or “patient” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the methods andcompositions provided herein, the mammal is a human.

The terms “disease” or “condition” refer to a state of being or healthstatus of a patient or subject capable of being treated with thecompounds or methods provided herein. In embodiments, the disease is adisease related to (e.g. caused by) Olig2 or aberrant Olig2 activity(e.g. brain cancer, glioblastoma multiforme, medulloblastoma,astrocytomas, brain stem gliomas, meningiomas, oligodendrogliomas,melanomas, lung cancers, breast cancer, leukemias, or Down's Syndrome).Examples of diseases, disorders, or conditions include, but are notlimited to brain cancer, glioblastoma multiforme, medulloblastoma,astrocytomas, brain stem gliomas, meningiomas, oligodendrogliomas,melanomas, lung cancers, breast cancer, leukemias, Down's Syndrome,colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma,Alzheimer's disease, Parkinson's disease, Huntington's Disease,frontotemporal dementia, Creutzfeldt-Jakob disease,Gerstmann-Straussler-Scheinker syndrome, prion disease,neurodegenerative diseases, cancer, cardiovascular disease,hypertension, Syndrome X, depression, anxiety, glaucoma, humanimmunodeficiency virus (HIV) or acquired immunodeficiency syndrome(AIDS), neurodegeneration, Alzheimer's disease, Parkinson's disease,cognition enhancement, Cushing's Syndrome, Addison's Disease,osteoporosis, frailty, muscle frailty, inflammatory diseases,osteoarthritis, rheumatoid arthritis, asthma and rhinitis, adrenalfunction-related ailments, viral infection, immunodeficiency,immunomodulation, autoimmune diseases, allergies, wound healing,compulsive behavior, multi-drug resistance, addiction, psychosis,anorexia, cachexia, post-traumatic stress syndrome, post-surgical bonefracture, medical catabolism, major psychotic depression, mild cognitiveimpairment, psychosis, dementia, hyperglycemia, stress disorders,antipsychotic induced weight gain, delirium, cognitive impairment indepressed patients, cognitive deterioration in individuals with Down'ssyndrome, psychosis associated with interferon-alpha therapy, chronicpain, pain associated with gastroesophageal reflux disease, postpartumpsychosis, postpartum depression, neurological disorders in prematureinfants, migraine headaches, stroke, aneurysm, brain aneurysm, cerebralaneurysm, brain attack, cerebrovascular accident, ischemia, thrombosis,arterial embolism, hemorrhage, transient ischemic attack, anemia,embolism, systemic hypoperfusion, venous thrombosis, arthritis,reperfusion injury, skin diseases or conditions, acne, acne vulgaris,keratosis pilaris, acute, promyelocytic leukemia, baldness, acnerosacea, harlequin ichthyosis, xeroderma pigmentosum, keratoses,neuroblastoma, fibrodysplasia ossificans progressive, eczema, rosacea,sun damage, wrinkles, or cosmetic conditions. In some instances,“disease” or “condition” refer to cancer. In some further instances,“cancer” refers to human cancers and carcinomas, sarcomas,adenocarcinomas, lymphomas, leukemias, etc., including solid andlymphoid cancers, kidney, breast, lung, bladder, colon, ovarian,prostate, pancreas, stomach, brain, head and neck, skin, uterine,testicular, glioma, esophagus, and liver cancer, includinghepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma,non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Celllymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML),or multiple myeloma.

As used herein, the term “cancer” refers to all types of cancer,neoplasm or malignant tumors found in mammals, including leukemia,carcinomas and sarcomas. Exemplary cancers that may be treated with acompound or method provided herein include cancer of the thyroid,endocrine system, brain, breast, cervix, colon, head & neck, liver,kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary,sarcoma, stomach, uterus or Medulloblastoma. Additional examplesinclude, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma,neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer,rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia,primary brain tumors, cancer, malignant pancreatic insulanoma, malignantcarcinoid, urinary bladder cancer, premalignant skin lesions, testicularcancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer,genitourinary tract cancer, malignant hypercalcemia, endometrial cancer,adrenal cortical cancer, neoplasms of the endocrine or exocrinepancreas, medullary thyroid cancer, medullary thyroid carcinoma,melanoma, colorectal cancer, papillary thyroid cancer, hepatocellularcarcinoma, or prostate cancer.

The term “leukemia” refers broadly to progressive, malignant diseases ofthe blood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number abnormal cells in the blood-leukemic or aleukemic(subleukemic). Exemplary leukemias that may be treated with a compoundor method provided herein include, for example, acute nonlymphocyticleukemia, chronic lymphocytic leukemia, acute granulocytic leukemia,chronic granulocytic leukemia, acute promyelocytic leukemia, adultT-cell leukemia, aleukemic leukemia, a leukocythemic leukemia,basophylic leukemia, blast cell leukemia, bovine leukemia, chronicmyelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilicleukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia,acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia,lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia,megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia,myeloblastic leukemia, myelocytic leukemia, myeloid granulocyticleukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cellleukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, or undifferentiated cell leukemia.

The term “sarcoma” generally refers to a tumor which is made up of asubstance like the embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas that may be treated with a compound or methodprovided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma,melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adiposesarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma,botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma,Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing'ssarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma,granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmentedhemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma,immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma,Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymomasarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma,serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas that may betreated with a compound or method provided herein include, for example,acral-lentiginous melanoma, amelanotic melanoma, benign juvenilemelanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma,juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodularmelanoma, subungal melanoma, or superficial spreading melanoma.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas that may be treated with acompound or method provided herein include, for example, medullarythyroid carcinoma, familial medullary thyroid carcinoma, acinarcarcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cysticcarcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolarcarcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinomabasocellulare, basaloid carcinoma, basosquamous cell carcinoma,bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogeniccarcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorioniccarcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma,cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum,cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma,carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoidcarcinoma, carcinoma epitheliale adenoides, exophytic carcinoma,carcinoma ex ulcere, carcinoma fibrosum, gelatinifomi carcinoma,gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare,glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma,hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma,hyaline carcinoma, hypernephroid carcinoma, infantile embryonalcarcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelialcarcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cellcarcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatouscarcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullarycarcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma,carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma,carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes,nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans,osteoid carcinoma, papillary carcinoma, periportal carcinoma,preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma,renal cell carcinoma of kidney, reserve cell carcinoma, carcinomasarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinomascroti, signet-ring cell carcinoma, carcinoma simplex, small-cellcarcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cellcarcinoma, carcinoma spongiosum, squamous carcinoma, squamous cellcarcinoma, string carcinoma, carcinoma telangiectaticum, carcinomatelangiectodes, transitional cell carcinoma, carcinoma tuberosum,tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

A “cancer associated with aberrant Olig2 activity” (also referred toherein as “Olig2 related cancer”) is a cancer caused by aberrant Olig2activity (e.g. a mutated Olig2 gene). Olig2 related cancers may includebrain cancer, glioblastoma multiforme, medulloblastoma, astrocytomas,brain stem gliomas, meningiomas, oligodendrogliomas, melanomas, lungcancers, breast cancer, leukemias, T cell leukemias.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying causes of symptoms, inhibiting the disease or condition,e.g., arresting the development of the disease or condition, relievingthe disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically. For example, in certain methodspresented herein successfully treat cancer by decreasing the incidenceof cancer and or causing remission of cancer. In some embodiments,certain methods presented herein successfully treat Down's Syndrome bydecreasing the incidence of Down's Syndrome or reducing one or moresymptoms of Down's Syndrome or reducing the severity of one or moresymptoms of Down's Syndrome.

As used herein, amelioration of the symptoms of a particular disease,disorder or condition by administration of a particular compound orpharmaceutical composition refers to any lessening of severity, delay inonset, slowing of progression, or shortening of duration, whetherpermanent or temporary, lasting or transient that can be attributed toor associated with administration of the compound or composition.

The term “modulate,” as used herein, means to interact with a targetprotein either directly or indirectly so as to alter the activity of thetarget protein, including, by way of example only, to inhibit theactivity of the target, or to limit or reduce the activity of thetarget.

As used herein, the term “modulator” refers to a compound that alters anactivity of a target. For example, a modulator can cause an increase ordecrease in the magnitude of a certain activity of a target compared tothe magnitude of the activity in the absence of the modulator. Incertain embodiments, a modulator is an inhibitor, which decreases themagnitude of one or more activities of a target. In certain embodiments,an inhibitor completely prevents one or more activities of a target. Insome embodiments, an Olig2 modulator is a compound that reduces theactivity of Olig2 in a cell. In some embodiments, an Olig2 diseasemodulator is a compound that reduces the severity of one or moresymptoms of a disease associated with Olig2 (e.g. cancer or Down'sSyndrome).

As used herein, the term “target activity” refers to a biologicalactivity capable of being modulated by a modulator. Certain exemplarytarget activities include, but are not limited to, binding affinity,signal transduction, enzymatic activity, tumor growth, inflammation orinflammation-related processes, and amelioration of one or more symptomsassociated with a disease or condition.

The terms “inhibits”, “inhibiting”, or “inhibitor” of Olig2 activity, asused herein, refer to inhibition of oligodendrocyte trasnsciption factor2 activity. In reference to a protein-inhibitor interaction the termsmean negatively affecting (e.g. decreasing) the activity or function ofthe protein (e.g. decreasing gene transcription regulated by Olig2)relative to the activity or function of the protein (e.g. Olig2,transcription factor) in the absence of the inhibitor (e.g. Olig2inhibitor or Olig2 inhibitor compound). In some embodiments inhibitionrefers to reduction of a disease or symptoms of disease. In someembodiments, inhibition refers to a reduction in the activity of asignal transduction pathway or signaling pathway (e.g. reduction of apathway involving transcription regulation by Olig2 or transcriptionregulated by Olig2). Thus, inhibition includes, at least in part,partially or totally blocking stimulation, decreasing, preventing, ordelaying activation, or inactivating, desensitizing, or down-regulatingsignal transduction or enzymatic activity or the amount of a protein(e.g. Olig2). In some embodiments, inhibition refers to inhibition ofOlig2.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

By “pharmaceutically acceptable,” as used herein, refers a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that one activeingredient, e.g. a compound of Formula (I), (II), (III), or (IV), and aco-agent, are both administered to a patient simultaneously in the formof a single entity or dosage. The term “non-fixed combination” meansthat one active ingredient, e.g. a compound of Formula (I), (II), (III),or (IV), and a co-agent, are administered to a patient as separateentities either simultaneously, concurrently or sequentially with nospecific intervening time limits, wherein such administration provideseffective levels of the two compounds in the body of the patient. Thelatter also applies to cocktail therapy, e.g. the administration ofthree or more active ingredients.

The term “pharmaceutical composition” refers to a mixture of a compoundof Formula (I), (II), (III), or (IV) described herein with otherchemical components, such as carriers, stabilizers, diluents, dispersingagents, suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. Multiple techniques of administering a compound exist inthe art including, but not limited to: intravenous, oral, aerosol,parenteral, ophthalmic, pulmonary and topical administration.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition that includes a compound of Formula (I), (II), (III), or(IV) described herein required to provide a clinically significantdecrease in disease symptoms. An appropriate “effective” amount in anyindividual case may be determined using techniques, such as a doseescalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules, or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated, however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents which can beproduced in the reaction mixture. The term “contacting” may includeallowing two species to react, interact, or physically touch, whereinthe two species may be a compound as described herein and a protein orenzyme (e.g. Olig2). In some embodiments, the protein may be Olig2. Insome embodiments contacting includes allowing a compound describedherein to interact with a protein or enzyme that is involved intranscription.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The term “excipient” or “carrier,” as used herein, refers to relativelynontoxic chemical compounds or agents that facilitate the incorporationof a compound into cells or tissues.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions (which also can provide pH controlor maintenance) are utilized as diluents in the art, including, but notlimited to a phosphate buffered saline solution.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Further information on metabolism may be obtainedfrom The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill(1996). Metabolites of the compounds disclosed herein can be identifiedeither by administration of compounds to a host and analysis of tissuesamples from the host, or by incubation of compounds with hepatic cellsin vitro and analysis of the resulting compounds.

“Bioavailability” refers to the percentage of the weight of the compounddisclosed herein (e.g. compound of Formula (I), (II), (III), or (IV)),that is delivered into the general circulation of the animal or humanbeing studied. The total exposure (AUC(0−∞)) of a drug when administeredintravenously is usually defined as 100% bioavailable (F %). “Oralbioavailability” refers to the extent to which a compound disclosedherein, is absorbed into the general circulation when the pharmaceuticalcomposition is taken orally as compared to intravenous injection.

“Blood plasma concentration” refers to the concentration of a compoundof Formula (I), (II), (III), or (IV) disclosed herein, in the plasmacomponent of blood of a subject. It is understood that the plasmaconcentration of compounds described herein may vary significantlybetween subjects, due to variability with respect to metabolism and/orpossible interactions with other therapeutic agents. In accordance withone embodiment disclosed herein, the blood plasma concentration of thecompounds disclosed herein may vary from subject to subject. Likewise,values such as maximum plasma concentration (Cmax) or time to reachmaximum plasma concentration (Tmax), or total area under the plasmaconcentration time curve (AUC(0−∞)) may vary from subject to subject.Due to this variability, the amount necessary to constitute “atherapeutically effective amount” of a compound may vary from subject tosubject.

As used herein, “amelioration” refers to an improvement in a disease orcondition or at least a partial relief of symptoms associated with adisease or condition.

As used herein, “immune cells” include cells of the immune system andcells that perform a function or activity in an immune response, suchas, but not limited to, T-cells, B-cells, lymphocytes, macrophages,dendritic cells, neutrophils, eosinophils, basophils, mast cells, plasmacells, white blood cells, antigen presenting cells and natural killercells.

Treatment Methods

In another aspect is a pharmaceutical composition comprising a compoundof Formula (I), (II), (III), or (IV), or a pharmaceutically acceptablesalt, solvate, or prodrug thereof, and at least one pharmaceuticallyacceptable excipient.

In another aspect is the use of a compound of Formula (I), (II), (III),or (IV), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or a pharmaceutically acceptable prodrug thereof,for the formulation of a medicament for inhibiting the activity of Olig2in a cell is provided. The method includes contacting the cell with acompound of Formula (I), (II), (III), or (IV), including embodimentsthereof.

In a further aspect is a method of treating a disease, disorder orcondition in a subject that would benefit from inhibition of Olig2activity comprising administering to the subject in need thereof acomposition comprising a compound of Formula (I), (II), (III), or (IV),or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Insome embodiments is a method of treating a disease, disorder orcondition in a subject that would benefit from inhibition of Olig2activity comprising administering to the subject in need thereof acomposition comprising a compound of Formula (I), (II), (III), or (IV),or a pharmaceutically acceptable salt, solvate, or prodrug thereof;wherein the disease is cancer or Down's Syndrome.

In another aspect is a method for treating a disease in a subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (I), (II), (III), or (IV), or apharmaceutically acceptable salt, solvate, or prodrug thereof, whereinthe disease is cancer or Down's Syndrome. In some embodiments is amethod for treating cancer in a subject comprising administering to thesubject in need thereof a composition comprising a compound of Formula(I), (II), (III), or (IV), or a pharmaceutically acceptable salt,solvate, or prodrug thereof. In some embodiments is a method fortreating Down's Syndrome in a subject comprising administering to thesubject in need thereof a composition comprising a compound of Formula(I), (II), (III), or (IV), or a pharmaceutically acceptable salt,solvate, or prodrug thereof.

In another embodiment is a method for treating cancer in a subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (I), (II), (III), or (IV), or apharmaceutically acceptable salt, solvate, or prodrug thereof, whereinthe cancer is brain cancer, glioblastoma multiforme, medulloblastoma,astrocytomas, brain stem gliomas, meningiomas, oligodendrogliomas,melanoma, lung cancer, breast cancer, or leukemia.

In another aspect is a method of inhibiting the activity of Olig2 in acell comprising contacting the cell with a compound of Formula (I),(II), (III), or (IV), or a pharmaceutically acceptable salt, solvate, orprodrug thereof.

In another aspect is the use of a compound of Formula (I), (II), (III),or (IV) or a pharmaceutically acceptable salt, solvate, or prodrugthereof, in the manufacture of a medicament for the treatment of adisease, disorder, or condition that would benefit from inhibition ofOlig2 activity.

In one aspect, provided herein is a pharmaceutical composition, whichincludes an effective amount of a compound provided herein, and apharmaceutically acceptable excipient. In a further aspect, provided arecompositions further including a second pharmaceutically activeingredient.

In certain embodiments, provided herein is a pharmaceutical compositioncontaining: i) a physiologically acceptable carrier, diluent, and/orexcipient; and ii) one or more compounds described herein.

In any of the aforementioned aspects are further embodiments thatinclude single administrations of the effective amount of the compoundsdisclosed herein, including further embodiments in which: (i) thecompound of Formula (I), (II), (III), or (IV) is administered once; (ii)the compound of Formula (I), (II), (III), or (IV) is administered to themammal multiple times over the span of one day; (iii) continually; or(iv) continuously.

In any of the aforementioned aspects are further embodiments thatinclude multiple administrations of the effective amount of the compoundof Formula (I), (II), (III), or (IV), including further embodiments inwhich (i) the compound of Formula (I), (II), (III), or (IV) isadministered in a single dose; (ii) the time between multipleadministrations is every 6 hours; (iii) the compound of Formula (I),(II), (III), or (IV) is administered to the mammal every 8 hours. Infurther or alternative embodiments, the method comprises a drug holiday,wherein the administration of the compound of Formula (I), (II), (III),or (IV) is temporarily suspended or the dose of the compound of Formula(I), (II), (III), or (IV) being administered is temporarily reduced; atthe end of the drug holiday, dosing of the compound of Formula (I),(II), (III), or (IV) is resumed. The length of the drug holiday can varyfrom 2 days to 1 year.

In one aspect, compounds described herein are administered to a human.In some embodiments, compounds described herein are orally administered.

Examples of Pharmaceutical Compositions and Methods of Administration

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen.Additional details about suitable excipients for pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference for such disclosure.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula (I), (II), (III), or (IV) described herein, withother chemical components, such as carriers, stabilizers, diluents,dispersing agents, suspending agents, thickening agents, and/orexcipients. The pharmaceutical composition facilitates administration ofthe compound to an organism. In practicing the methods of treatment oruse provided herein, therapeutically effective amounts of compoundsdescribed herein are administered in a pharmaceutical composition to amammal having a disease, disorder, or condition to be treated. In someembodiments, the mammal is a human. A therapeutically effective amountcan vary widely depending on the severity of the disease, the age andrelative health of the subject, the potency of the compound used andother factors. The compounds of Formula (I), (II), (III), or (IV) can beused singly or in combination with one or more therapeutic agents ascomponents of mixtures (as in combination therapy).

The pharmaceutical formulations described herein can be administered toa subject by multiple administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. Moreover, the pharmaceutical compositions described herein,which include a compound of Formula (I), (II), (III), or (IV) describedherein, can be formulated into any suitable dosage form, including butnot limited to, aqueous oral dispersions, liquids, gels, syrups,elixirs, slurries, suspensions, aerosols, controlled releaseformulations, fast melt formulations, effervescent formulations,lyophilized formulations, tablets, powders, pills, dragees, capsules,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediaterelease and controlled release formulations.

One may administer the compounds and/or compositions in a local ratherthan systemic manner, for example, via injection of the compounddirectly into an organ or tissue, often in a depot preparation orsustained release formulation. Such long acting formulations may beadministered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Furthermore, one mayadminister the drug in a targeted drug delivery system, for example, ina liposome coated with organ-specific antibody. The liposomes will betargeted to and taken up selectively by the organ. In addition, the drugmay be provided in the form of a rapid release formulation, in the formof an extended release formulation, or in the form of an intermediaterelease formulation.

Pharmaceutical compositions including a compound described herein may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The pharmaceutical compositions will include at least one compound ofFormula (I), (II), (III), or (IV) described herein, as an activeingredient in free-acid or free-base form, or in a pharmaceuticallyacceptable salt form. In addition, the methods and pharmaceuticalcompositions described herein include the use of crystalline forms (alsoknown as polymorphs), as well as active metabolites of these compoundshaving the same type of activity. In some situations, compounds mayexist as tautomers. All tautomers are included within the scope of thecompounds presented herein. Additionally, the compounds described hereincan exist in unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein.

In certain embodiments, compositions provided herein may also includeone or more preservatives to inhibit microbial activity. Suitablepreservatives include quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein (e.g. compounds of Formula (I), (II), (III), or (IV)), optionallygrinding the resulting mixture, and processing the mixture of granules,after adding suitable auxiliaries, if desired, to obtain tablets, pills,or capsules. Suitable excipients include, for example, fillers such assugars, including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methylcellulose,microcrystalline cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP orpovidone) or calcium phosphate. If desired, disintegrating agents may beadded, such as the cross-linked croscarmellose sodium,polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such assodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added.

In some embodiments, the solid dosage forms disclosed herein may be inthe form of a tablet, (including a suspension tablet, a fast-melttablet, a bite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder), acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form, controlledrelease formulations, pulsatile release dosage forms, multiparticulatedosage forms, pellets, granules, or an aerosol. In other embodiments,the pharmaceutical formulation is in the form of a powder. In stillother embodiments, the pharmaceutical formulation is in the form of atablet, including but not limited to, a fast-melt tablet. Additionally,pharmaceutical formulations of the compounds described herein may beadministered as a single capsule or in multiple capsule dosage form. Insome embodiments, the pharmaceutical formulation is administered in two,or three, or four, capsules or tablets.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of a compound ofFormula (I), (II), (III), or (IV) described herein, with one or morepharmaceutical excipients to form a bulk blend composition. Whenreferring to these bulk blend compositions as homogeneous, it is meantthat the particles of the compound of Formula (I), (II), (III), or (IV)described herein, are dispersed evenly throughout the composition sothat the composition may be subdivided into equally effective unitdosage forms, such as tablets, pills, and capsules. The individual unitdosages may also include film coatings, which disintegrate upon oralingestion or upon contact with diluent. These formulations can bemanufactured by conventional pharmacological techniques.

The pharmaceutical solid dosage forms described herein can include acompound of Formula (I), (II), (III), or (IV) described herein, and oneor more pharmaceutically acceptable additives such as a compatiblecarrier, binder, filling agent, suspending agent, flavoring agent,sweetening agent, disintegrating agent, dispersing agent, surfactant,lubricant, colorant, diluent, solubilizer, moistening agent,plasticizer, stabilizer, penetration enhancer, wetting agent,anti-foaming agent, antioxidant, preservative, or one or morecombination thereof. In still other aspects, using standard coatingprocedures, such as those described in Remington's PharmaceuticalSciences, 20th Edition (2000), a film coating is provided around theformulation of the compound described herein. In one embodiment, some orall of the particles of the compound described herein are coated. Inanother embodiment, some or all of the particles of the compounddescribed herein are microencapsulated. In still another embodiment, theparticles of the compound described herein are not microencapsulated andare uncoated.

Suitable carriers for use in the solid dosage forms described hereininclude, but are not limited to, acacia, gelatin, colloidal silicondioxide, calcium glycerophosphate, calcium lactate, maltodextrin,glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodiumchloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyllactylate, carrageenan, monoglyceride, diglyceride, pregelatinizedstarch, hydroxypropylmethyl cellulose, hydroxypropylmethyl celluloseacetate stearate, sucrose, microcrystalline cellulose, lactose, mannitoland the like.

Suitable filling agents for use in the solid dosage forms describedherein include, but are not limited to, lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, hydroxypropylmethycellulose(HPMC), hydroxypropylmethycellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose,xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethyleneglycol, and the like.

In order to release the compound of Formula (I), (II), (III), or (IV)from a solid dosage form matrix as efficiently as possible,disintegrants are often used in the formulation, especially when thedosage forms are compressed with binder. Disintegrants help rupturingthe dosage form matrix by swelling or capillary action when moisture isabsorbed into the dosage form. Suitable disintegrants for use in thesolid dosage forms described herein include, but are not limited to,natural starch such as corn starch or potato starch, a pregelatinizedstarch such as National 1551 or Amijel®, or sodium starch glycolate suchas Promogel® or Explotab®, a cellulose such as a wood product,methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel®PH102, Avicel® PH105, Elcema P100, Emcocel®, Vivacel®, Ming Tia®, andSolka-Floc®, methylcellulose, croscarmellose, or a cross-linkedcellulose, such as cross-linked sodium carboxymethylcellulose(Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linkedcroscarmellose, a cross-linked starch such as sodium starch glycolate, across-linked polymer such as crospovidone, a cross-linkedpolyvinylpyrrolidone, alginate such as alginic acid or a salt of alginicacid such as sodium alginate, a clay such as Veegum® HV (magnesiumaluminum silicate), a gum such as agar, guar, locust bean, Karaya,pectin, or tragacanth, sodium starch glycolate, bentonite, a naturalsponge, a surfactant, a resin such as a cation-exchange resin, citruspulp, sodium lauryl sulfate, sodium lauryl sulfate in combinationstarch, and the like.

Binders impart cohesiveness to solid oral dosage form formulations: forpowder filled capsule formulation, they aid in plug formation that canbe filled into soft or hard shell capsules and for tablet formulation,they ensure the tablet remaining intact after compression and helpassure blend uniformity prior to a compression or fill step. Materialssuitable for use as binders in the solid dosage forms described hereininclude, but are not limited to, carboxymethylcellulose, methylcellulose(e.g., Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USPPharmacoat-603, hydroxypropylmethylcellulose acetate stearate (AqoateHS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g.,Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystallinecellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesiumaluminum silicate, polysaccharide acids, bentonites, gelatin,polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone,starch, pregelatinized starch, tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such asacacia, tragacanth, ghatti gum, mucilage of isapol husks, starch,polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone®XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethyleneglycol, waxes, sodium alginate, and the like.

In general, binder levels of 20-70% are used in powder-filled gelatincapsule formulations. Binder usage level in tablet formulations varieswhether direct compression, wet granulation, roller compaction, or usageof other excipients such as fillers which itself can act as moderatebinder. In some embodiments, formulators determine the binder level forthe formulations, but binder usage level of up to 70% in tabletformulations is common.

Suitable lubricants or glidants for use in the solid dosage formsdescribed herein include, but are not limited to, stearic acid, calciumhydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal andalkaline earth metal salts, such as aluminum, calcium, magnesium, zinc,stearic acid, sodium stearates, magnesium stearate, zinc stearate,waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol or a methoxypolyethylene glycolsuch as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol,sodium oleate, glyceryl behenate, glyceryl palmitostearate, glycerylbenzoate, magnesium or sodium lauryl sulfate, and the like.

Suitable diluents for use in the solid dosage forms described hereininclude, but are not limited to, sugars (including lactose, sucrose, anddextrose), polysaccharides (including dextrates and maltodextrin),polyols (including mannitol, xylitol, and sorbitol), cyclodextrins andthe like.

Suitable wetting agents for use in the solid dosage forms describedherein include, for example, oleic acid, glyceryl monostearate, sorbitanmonooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodiumoleate, sodium lauryl sulfate, magnesium stearate, sodium docusate,triacetin, vitamin E TPGS and the like.

Suitable surfactants for use in the solid dosage forms described hereininclude, for example, sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bilesalts, glyceryl monostearate, copolymers of ethylene oxide and propyleneoxide, e.g., Pluronic® (BASF), and the like.

Suitable suspending agents for use in the solid dosage forms describedhere include, but are not limited to, polyvinylpyrrolidone, e.g.,polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., thepolyethylene glycol can have a molecular weight of about 300 to about6000, or about 3350 to about 4000, or about 5400 to about 7000, vinylpyrrolidone/vinyl acetate copolymer (S630), sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethyl cellulose,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethyl cellulose, hydroxyethyl cellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described hereininclude, for example, e.g., butylated hydroxytoluene (BHT), sodiumascorbate, and tocopherol.

There is considerable overlap between additives used in the solid dosageforms described herein. Thus, the above-listed additives should be takenas merely exemplary, and not limiting, of the types of additives thatcan be included in solid dosage forms of the pharmaceutical compositionsdescribed herein.

In other embodiments, one or more layers of the pharmaceuticalformulation are plasticized. Illustratively, a plasticizer is generallya high boiling point solid or liquid. Suitable plasticizers can be addedfrom about 0.01% to about 50% by weight (w/w) of the coatingcomposition. Plasticizers include, but are not limited to, diethylphthalate, citrate esters, polyethylene glycol, glycerol, acetylatedglycerides, triacetin, polypropylene glycol, polyethylene glycol,triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, andcastor oil.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend of the formulations described above. In various embodiments,compressed tablets which are designed to dissolve in the mouth willinclude one or more flavoring agents. In other embodiments, thecompressed tablets will include a film surrounding the final compressedtablet. In some embodiments, the film coating can provide a delayedrelease of the compounds of Formula (I), (II), (III), or (IV) describedherein from the formulation. In other embodiments, the film coating aidsin patient compliance (e.g., Opadry® coatings or sugar coating). Filmcoatings including Opadry® typically range from about 1% to about 3% ofthe tablet weight. In other embodiments, the compressed tablets includeone or more excipients.

A capsule may be prepared, for example, by placing the bulk blend of theformulation of the compound described above, inside of a capsule. Insome embodiments, the formulations (non-aqueous suspensions andsolutions) are placed in a soft gelatin capsule. In other embodiments,the formulations are placed in standard gelatin capsules or non-gelatincapsules such as capsules comprising HPMC. In other embodiments, theformulation is placed in a sprinkle capsule, wherein the capsule may beswallowed whole or the capsule may be opened and the contents sprinkledon food prior to eating. In some embodiments, the therapeutic dose issplit into multiple (e.g., two, three, or four) capsules. In someembodiments, the entire dose of the formulation is delivered in acapsule form.

In various embodiments, the particles of the compound of Formula (I),(II), (III), or (IV) described herein and one or more excipients are dryblended and compressed into a mass, such as a tablet, having a hardnesssufficient to provide a pharmaceutical composition that substantiallydisintegrates within less than about 30 minutes, less than about 35minutes, less than about 40 minutes, less than about 45 minutes, lessthan about 50 minutes, less than about 55 minutes, or less than about 60minutes, after oral administration, thereby releasing the formulationinto the gastrointestinal fluid.

In another aspect, dosage forms may include microencapsulatedformulations. In some embodiments, one or more other compatiblematerials are present in the microencapsulation material. Exemplarymaterials include, but are not limited to, pH modifiers, erosionfacilitators, anti-foaming agents, antioxidants, flavoring agents, andcarrier materials such as binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, and diluents.

Materials useful for the microencapsulation described herein includematerials compatible with compounds described herein, which sufficientlyisolate the compound from other non-compatible excipients. Materialscompatible with compounds described herein are those that delay therelease of the compounds of Formula (I), (II), (III), or (IV) in vivo.

Exemplary microencapsulation materials useful for delaying the releaseof the formulations including compounds described herein, include, butare not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel®or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC),hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC,Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, BenecelMP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A,hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS)and Metolose®, Ethylcelluloses (EC) and mixtures thereof such as E461,Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such asOpadry AMB, hydroxyethylcelluloses such as Natrosol®,carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) suchas Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol co-polymerssuch as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX),polyethylene glycols, modified food starch, acrylic polymers andmixtures of acrylic polymers with cellulose ethers such as Eudragit®EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit®L100, Eudragit® S100, Eudragit® RD 100, Eudragit® E100, Eudragit® L12.5,Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, celluloseacetate phthalate, sepifilms such as mixtures of HPMC and stearic acid,cyclodextrins, and mixtures of these materials.

In still other embodiments, plasticizers such as polyethylene glycols,e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800,stearic acid, propylene glycol, oleic acid, and triacetin areincorporated into the microencapsulation material. In other embodiments,the microencapsulating material useful for delaying the release of thepharmaceutical compositions is from the USP or the National Formulary(NF). In yet other embodiments, the microencapsulation material isKlucel. In still other embodiments, the microencapsulation material ismethocel.

Microencapsulated compounds described herein may be formulated bymethods that include, e.g., spray drying processes, spinningdisk-solvent processes, hot melt processes, spray chilling methods,fluidized bed, electrostatic deposition, centrifugal extrusion,rotational suspension separation, polymerization at liquid-gas orsolid-gas interface, pressure extrusion, or spraying solvent extractionbath. In addition to these, several chemical techniques, e.g., complexcoacervation, solvent evaporation, polymer-polymer incompatibility,interfacial polymerization in liquid media, in situ polymerization,in-liquid drying, and desolvation in liquid media could also be used.Furthermore, other methods such as roller compaction,extrusion/spheronization, coacervation, or nanoparticle coating may alsobe used.

In still other embodiments, effervescent powders are also prepared inaccordance with the present disclosure. Effervescent salts have beenused to disperse medicines in water for oral administration.Effervescent salts are granules or coarse powders containing a medicinalagent in a dry mixture, usually composed of sodium bicarbonate, citricacid and/or tartaric acid. When such salts are added to water, the acidsand the base react to liberate carbon dioxide gas, thereby causing“effervescence.” Examples of effervescent salts include, e.g., thefollowing ingredients: sodium bicarbonate or a mixture of sodiumbicarbonate and sodium carbonate, citric acid and/or tartaric acid. Anyacid-base combination that results in the liberation of carbon dioxidecan be used in place of the combination of sodium bicarbonate and citricand tartaric acids, as long as the ingredients were suitable forpharmaceutical use and result in a pH of about 6.0 or higher.

In other embodiments, the formulations described herein, which include acompound described herein, are solid dispersions. Methods of producingsuch solid dispersions include, but are not limited to, for example,U.S. Pat. Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269,and U.S. patent publication no. 2004/0013734. In still otherembodiments, the formulations described herein are solid solutions.Solid solutions incorporate a substance together with the active agentand other excipients such that heating the mixture results indissolution of the drug and the resulting composition is then cooled toprovide a solid blend which can be further formulated or directly addedto a capsule or compressed into a tablet. Methods of producing suchsolid solutions include, but are not limited to, for example, U.S. Pat.Nos. 4,151,273, 5,281,420, and 6,083,518.

The pharmaceutical solid oral dosage forms including formulationsdescribed herein, which include a compounds described herein, can befurther formulated to provide a controlled release of the compound ofFormula (I), (II), (III), or (IV). Controlled release refers to therelease of the compounds described herein from a dosage form in which itis incorporated according to a desired profile over an extended periodof time. Controlled release profiles include, for example, sustainedrelease, prolonged release, pulsatile release, and delayed releaseprofiles. In contrast to immediate release compositions, controlledrelease compositions allow delivery of an agent to a subject over anextended period of time according to a predetermined profile. Suchrelease rates can provide therapeutically effective levels of agent foran extended period of time and thereby provide a longer period ofpharmacologic response while minimizing side effects as compared toconventional rapid release dosage forms. Such longer periods of responseprovide for many inherent benefits that are not achieved with thecorresponding short acting, immediate release preparations.

In some embodiments, the solid dosage forms described herein can beformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to affect release in the smallintestine of the gastrointestinal tract. The enteric coated dosage formmay be a compressed or molded or extruded tablet/mold (coated oruncoated) containing granules, powder, pellets, beads or particles ofthe active ingredient and/or other composition components, which arethemselves coated or uncoated. The enteric coated oral dosage form mayalso be a capsule (coated or uncoated) containing pellets, beads orgranules of the solid carrier or the composition, which are themselvescoated or uncoated.

The term “delayed release” as used herein refers to the delivery so thatthe release can be accomplished at some generally predictable locationin the intestinal tract more distal to that which would have beenaccomplished if there had been no delayed release alterations. In someembodiments the method for delay of release is coating. Any coatingsshould be applied to a sufficient thickness such that the entire coatingdoes not dissolve in the gastrointestinal fluids at pH below about 5,but does dissolve at pH about 5 and above. Coatings may be made from:

Acrylic polymers. The performance of acrylic polymers (primarily theirsolubility in biological fluids) can vary based on the degree and typeof substitution. Examples of suitable acrylic polymers includemethacrylic acid copolymers and ammonium methacrylate copolymers. TheEudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available assolubilized in organic solvent, aqueous dispersion, or dry powders. TheEudragit series RL, NE, and RS are insoluble in the gastrointestinaltract but are permeable and are used primarily for colonic targeting.The Eudragit series E dissolve in the stomach. The Eudragit series L,L-30D and S are insoluble in stomach and dissolve in the intestine;

Cellulose Derivatives. Examples of suitable cellulose derivatives are:ethyl cellulose; reaction mixtures of partial acetate esters ofcellulose with phthalic anhydride. The performance can vary based on thedegree and type of substitution. Cellulose acetate phthalate (CAP)dissolves in pH>6. Aquateric (FMC) is an aqueous based system and is aspray dried CAP pseudolatex with particles <1 μm. Other components inAquateric can include pluronics, Tweens, and acetylated monoglycerides.Other suitable cellulose derivatives include: cellulose acetatetrimellitate (Eastman); methylcellulose (Pharmacoat, Methocel);hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethylcellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetatesuccinate (e.g., AQOAT (Shin Etsu)). The performance can vary based onthe degree and type of substitution. For example, HPMCP such as, HP-50,HP-55, HP-55S, HP-55F grades are suitable. The performance can varybased on the degree and type of substitution. For example, suitablegrades of hydroxypropylmethylcellulose acetate succinate include, butare not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF),which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.These polymers are offered as granules, or as fine powders for aqueousdispersions;

Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH>5, and it ismuch less permeable to water vapor and gastric fluids.

In some embodiments, the coating can, and usually does, contain aplasticizer and possibly other coating excipients such as colorants,talc, and/or magnesium stearate. Suitable plasticizers include triethylcitrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethylcitrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethylphthalate, tributyl citrate, acetylated monoglycerides, glycerol, fattyacid esters, propylene glycol, and dibutyl phthalate. In particular,anionic carboxylic acrylic polymers usually will contain 10-25% byweight of a plasticizer, especially dibutyl phthalate, polyethyleneglycol, triethyl citrate and triacetin. Conventional coating techniquessuch as spray or pan coating are employed to apply coatings. The coatingthickness must be sufficient to ensure that the oral dosage form remainsintact until the desired site of topical delivery in the intestinaltract is reached.

Colorants, detackifiers, surfactants, antifoaming agents, lubricants(e.g., carnuba wax or PEG) may be added to the coatings besidesplasticizers to solubilize or disperse the coating material, and toimprove coating performance and the coated product.

In other embodiments, the formulations described herein, which include acompound of Formula (I), (II), (III), or (IV) described herein, aredelivered using a pulsatile dosage form. A pulsatile dosage form iscapable of providing one or more immediate release pulses atpredetermined time points after a controlled lag time or at specificsites. Pulsatile dosage forms may be administered using a variety ofpulsatile formulations including, but are not limited to, thosedescribed in U.S. Pat. Nos. 5,011,692; 5,017,381; 5,229,135; 5,840,329;4,871,549; 5,260,068; 5,260,069; 5,508,040; 5,567,441 and 5,837,284.

Many other types of controlled release systems are suitable for use withthe formulations described herein. Examples of such delivery systemsinclude, e.g., polymer-based systems, such as polylactic andpolyglycolic acid, polyanhydrides and polycaprolactone; porous matrices,nonpolymer-based systems that are lipids, including sterols, such ascholesterol, cholesterol esters and fatty acids, or neutral fats, suchas mono-, di- and triglycerides; hydrogel release systems; silasticsystems; peptide-based systems; wax coatings, bioerodible dosage forms,compressed tablets using conventional binders and the like. See, e.g.,Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214(1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2ndEd., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725; 4,624,848; 4,968,509;5,461,140; 5,456,923; 5,516,527; 5,622,721; 5,686,105; 5,700,410;5,977,175; 6,465,014; and 6,932,983.

In some embodiments, pharmaceutical formulations are provided thatinclude particles of the compounds described herein, e.g. compounds ofFormula (I), (II), (III), or (IV), and at least one dispersing agent orsuspending agent for oral administration to a subject. The formulationsmay be a powder and/or granules for suspension, and upon admixture withwater, a substantially uniform suspension is obtained.

Liquid formulation dosage forms for oral administration can be aqueoussuspensions selected from the group including, but not limited to,pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).

The aqueous suspensions and dispersions described herein can remain in ahomogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005edition, chapter 905), for at least 4 hours. The homogeneity should bedetermined by a sampling method consistent with regard to determininghomogeneity of the entire composition. In one embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 1 minute. In another embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 45 seconds. In yet another embodiment, anaqueous suspension can be re-suspended into a homogenous suspension byphysical agitation lasting less than 30 seconds. In still anotherembodiment, no agitation is necessary to maintain a homogeneous aqueousdispersion.

The pharmaceutical compositions described herein may include sweeteningagents such as, but not limited to, acacia syrup, acesulfame K, alitame,anise, apple, aspartame, banana, Bavarian cream, berry, black currant,butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream,chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream,cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate,cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey,isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate(MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mintcream, mixed berry, neohesperidine DC, neotame, orange, pear, peach,peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer,rum, saccharin, safrole, sorbitol, spearmint, spearmint cream,strawberry, strawberry cream, stevia, sucralose, sucrose, sodiumsaccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin,sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tuttifruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol,or any combination of these flavoring ingredients, e.g., anise-menthol,cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint,honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream,vanilla-mint, and mixtures thereof.

In some embodiments, the pharmaceutical formulations described hereincan be self-emulsifying drug delivery systems (SEDDS). Emulsions aredispersions of one immiscible phase in another, usually in the form ofdroplets. Generally, emulsions are created by vigorous mechanicaldispersion. SEDDS, as opposed to emulsions or microemulsions,spontaneously form emulsions when added to an excess of water withoutany external mechanical dispersion or agitation. An advantage of SEDDSis that only gentle mixing is required to distribute the dropletsthroughout the solution. Additionally, water or the aqueous phase can beadded just prior to administration, which ensures stability of anunstable or hydrophobic active ingredient. Thus, the SEDDS provides aneffective delivery system for oral and parenteral delivery ofhydrophobic active ingredients. SEDDS may provide improvements in thebioavailability of hydrophobic active ingredients. Methods of producingself-emulsifying dosage forms include, but are not limited to, forexample, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.

There is overlap between the above-listed additives used in the aqueousdispersions or suspensions described herein, since a given additive isoften classified differently by different practitioners in the field, oris commonly used for any of several different functions. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in formulationsdescribed herein.

Potential excipients for intranasal formulations include, for example,U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452. Formulationssolutions in saline, employing benzyl alcohol or other suitablepreservatives, fluorocarbons, and/or other solubilizing or dispersingagents. See, for example, Ansel, H. C. et al., Pharmaceutical DosageForms and Drug Delivery Systems, Sixth Ed. (1995). Preferably thesecompositions and formulations are prepared with suitable nontoxicpharmaceutically acceptable ingredients. The choice of suitable carriersis highly dependent upon the exact nature of the nasal dosage formdesired, e.g., solutions, suspensions, ointments, or gels. Nasal dosageforms generally contain large amounts of water in addition to the activeingredient. Minor amounts of other ingredients such as pH adjusters,emulsifiers or dispersing agents, preservatives, surfactants, gellingagents, or buffering and other stabilizing and solubilizing agents mayalso be present. Preferably, the nasal dosage form should be isotonicwith nasal secretions.

For administration by inhalation, the compounds described herein may bein a form as an aerosol, a mist or a powder. Pharmaceutical compositionsdescribed herein are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, such as, by way of example only, gelatin foruse in an inhaler or insufflator may be formulated containing a powdermix of the compound described herein and a suitable powder base such aslactose or starch.

Buccal formulations that include compounds described herein may beadministered using a variety of formulations which include, but are notlimited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and5,739,136. In addition, the buccal dosage forms described herein canfurther include a bioerodible (hydrolysable) polymeric carrier that alsoserves to adhere the dosage form to the buccal mucosa. The buccal dosageform is fabricated so as to erode gradually over a predetermined timeperiod, wherein the delivery of the compound is provided essentiallythroughout. Buccal drug delivery avoids the disadvantages encounteredwith oral drug administration, e.g., slow absorption, degradation of theactive agent by fluids present in the gastrointestinal tract and/orfirst-pass inactivation in the liver. With regard to the bioerodible(hydrolysable) polymeric carrier, virtually any such carrier can beused, so long as the desired drug release profile is not compromised,and the carrier is compatible with the compounds described herein, andany other components that may be present in the buccal dosage unit.Generally, the polymeric carrier comprises hydrophilic (water-solubleand water-swellable) polymers that adhere to the wet surface of thebuccal mucosa. Examples of polymeric carriers useful herein includeacrylic acid polymers and co, e.g., those known as “carbomers”(Carbopol®, which may be obtained from B.F. Goodrich, is one suchpolymer). Other components may also be incorporated into the buccaldosage forms described herein include, but are not limited to,disintegrants, diluents, binders, lubricants, flavoring, colorants,preservatives, and the like. For buccal or sublingual administration,the compositions may take the form of tablets, lozenges, or gelsformulated in a conventional manner.

Transdermal formulations described herein may be administered using avariety of devices including but not limited to, U.S. Pat. Nos.3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097,3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894,4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299,4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983,6,929,801 and 6,946,144.

The transdermal dosage forms described herein may incorporate certainpharmaceutically acceptable excipients which are conventional in theart. In one embodiment, the transdermal formulations described hereininclude at least three components: (1) a formulation of a compound of,(2) a penetration enhancer; and (3) an aqueous adjuvant. In addition,transdermal formulations can include additional components such as, butnot limited to, gelling agents, creams and ointment bases, and the like.In some embodiments, the transdermal formulation can further include awoven or non-woven backing material to enhance absorption and preventthe removal of the transdermal formulation from the skin. In otherembodiments, the transdermal formulations described herein can maintaina saturated or supersaturated state to promote diffusion into the skin.

Formulations suitable for transdermal administration of compoundsdescribed herein may employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents. Still further, transdermal deliveryof the compounds described herein can be accomplished by means ofiontophoretic patches and the like. Additionally, transdermal patchescan provide controlled delivery of the compounds described herein. Therate of absorption can be slowed by using rate-controlling membranes orby trapping the compound within a polymer matrix or gel. Conversely,absorption enhancers can be used to increase absorption. An absorptionenhancer or carrier can include absorbable pharmaceutically acceptablesolvents to assist passage through the skin. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound to the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Formulations suitable for intramuscular, subcutaneous, or intravenousinjection may include physiologically acceptable sterile aqueous ornon-aqueous solutions, dispersions, suspensions or emulsions, andsterile powders for reconstitution into sterile injectable solutions ordispersions. Examples of suitable aqueous and non-aqueous carriers,diluents, solvents, or vehicles including water, ethanol, polyols(propyleneglycol, polyethylene-glycol, glycerol, cremophor and thelike), suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants. Formulations suitable forsubcutaneous injection may also contain additives such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the growth ofmicroorganisms can be ensured by various antibacterial and antifungalagents, such as parabens, chlorobutanol, phenol, sorbic acid, and thelike. It may also be desirable to include isotonic agents, such assugars, sodium chloride, and the like. Prolonged absorption of theinjectable pharmaceutical form can be brought about by the use of agentsdelaying absorption, such as aluminum monostearate and gelatin.

For intravenous injections, compounds described herein may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally recognized in the field. For other parenteral injections,appropriate formulations may include aqueous or nonaqueous solutions,preferably with physiologically compatible buffers or excipients. Suchexcipients are generally recognized in the field.

Parenteral injections may involve bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical composition described herein may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, the compounds described herein may be administeredtopically and are formulated into a variety of topically administrablecompositions, such as solutions, suspensions, lotions, gels, pastes,medicated sticks, balms, creams or ointments. Such pharmaceuticalcompounds can contain solubilizers, stabilizers, tonicity enhancingagents, buffers and preservatives.

The compounds described herein may also be formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

Generally, an agent, such as a compound of Formula (I), (II), (III), or(IV), is administered in an amount effective for amelioration of, orprevention of the development of symptoms of, the disease or disorder(i.e., a therapeutically effective amount). Thus, a therapeuticallyeffective amount can be an amount that is capable of at least partiallypreventing or reversing a disease or disorder. The dose required toobtain an effective amount may vary depending on the agent, formulation,disease or disorder, and individual to whom the agent is administered.

Determination of effective amounts may also involve in vitro assays inwhich varying doses of agent are administered to cells in culture andthe concentration of agent effective for ameliorating some or allsymptoms is determined in order to calculate the concentration requiredin vivo. Effective amounts may also be based in in vivo animal studies.

An agent can be administered prior to, concurrently with and subsequentto the appearance of symptoms of a disease or disorder. In someembodiments, an agent is administered to a subject with a family historyof the disease or disorder, or who has a phenotype that may indicate apredisposition to a disease or disorder, or who has a genotype whichpredisposes the subject to the disease or disorder.

Examples of Methods of Dosing and Treatment Regimens

The compounds described herein can be used in the preparation ofmedicaments for the treatment of cancer, or for the treatment ofdiseases or conditions that would benefit, at least in part, from Olig2inhibition. In addition, a method for treating any of the diseases orconditions described herein in a subject in need of such treatment,involves administration of pharmaceutical compositions containing atleast one compound described herein, or a pharmaceutically acceptablesalt, pharmaceutically acceptable prodrug, or pharmaceuticallyacceptable solvate thereof, in therapeutically effective amounts to saidsubject.

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday may be from about 10%to about 100%, including, by way of example only, about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,about 85%, about 90%, about 95%, or about 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease orcondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be determined in amanner recognized in the field according to the particular circumstancessurrounding the case, including, e.g., the specific agent beingadministered, the route of administration, the condition being treated,and the subject or host being treated. In general, however, dosesemployed for adult human treatment will typically be in the range ofabout 0.02-about 5000 mg per day, in some embodiments, about 1-about1500 mg per day. The desired dose may conveniently be presented in asingle dose or as divided doses administered simultaneously (or over ashort period of time) or at appropriate intervals, for example as two,three, four or more sub-doses per day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The daily dosages appropriate for the compounds described hereindescribed herein are from about 0.01 mg/kg to about 20 mg/kg. In oneembodiment, the daily dosages are from about 0.1 mg/kg to about 10mg/kg. An indicated daily dosage in the larger mammal, including, butnot limited to, humans, is in the range from about 0.5 mg to about 1000mg, conveniently administered in a single dose or in divided doses,including, but not limited to, up to four times a day or in extendedrelease form. Suitable unit dosage forms for oral administration includefrom about 1 to about 500 mg active ingredient. In one embodiment, theunit dosage is about 1 mg, about 5 mg, about, 10 mg, about 20 mg, about50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about500 mg. The foregoing ranges are merely suggestive, as the number ofvariables in regard to an individual treatment regime is large, andconsiderable excursions from these recommended values are not uncommon.Such dosages may be altered depending on a number of variables, notlimited to the activity of the compound used, the disease or conditionto be treated, the mode of administration, the requirements of theindividual subject, the severity of the disease or condition beingtreated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Combination Treatments

The compounds of Formula (I), (II), (III), or (IV), and compositionsthereof, may also be used in combination with other therapeutic agentsthat are selected for their therapeutic value for the condition to betreated. In general, the compositions described herein and, inembodiments where combinational therapy is employed, other agents do nothave to be administered in the same pharmaceutical composition, and may,because of different physical and chemical characteristics, have to beadministered by different routes. The determination of the mode ofadministration and the advisability of administration, where possible,in the same pharmaceutical composition, is well within the knowledge ofthe clinician. The initial administration can be made according toestablished protocols recognized in the field, and then, based upon theobserved effects, the dosage, modes of administration and times ofadministration can be modified by the clinician.

In certain instances, it may be appropriate to administer at least onecompound described herein in combination with another therapeutic agent.By way of example only, if one of the side effects experienced by apatient upon receiving one of the compounds herein, such as a compoundof Formula (I), (II), (III), or (IV), is nausea, then it may beappropriate to administer an anti-nausea agent in combination with theinitial therapeutic agent. Or, by way of example only, the therapeuticeffectiveness of one of the compounds described herein may be enhancedby administration of an adjuvant (i.e., by itself the adjuvant may haveminimal therapeutic benefit, but in combination with another therapeuticagent, the overall therapeutic benefit to the patient is enhanced). Or,by way of example only, the benefit experienced by a patient may beincreased by administering one of the compounds described herein withanother therapeutic agent (which also includes a therapeutic regimen)that also has therapeutic benefit. In any case, regardless of thedisease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

For therapeutic applications, the compounds or drugs of the presentinvention can be administered alone or co-administered in combinationwith conventional chemotherapy, radiotherapy, hormonal therapy, and/orimmunotherapy.

As a non-limiting example, the compounds of Formula (I), (II), (III), or(IV) described herein can be co-administered with conventionalchemotherapeutic agents including alkylating agents (e.g.,cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan,mechlorethamine, uramustine, thiotepa, nitrosoureas, temozolomide,etc.), anti-metabolites (e.g., 5-fluorouracil, azathioprine,methotrexate, leucovorin, capecitabine, cytarabine, floxuridine,fludarabine, gemcitabine, pemetrexed, raltitrexed, etc.), plantalkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine,podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors(e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposidephosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin,adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin,mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g.cisplatin, oxaloplatin, carboplatin, etc.), and the like. In someembodiments, a compound of Formula (I), (II), (III), or (IV) describedherein is co-administered in combination with conventional chemotherapyand radiotherapy. In some embodiments, a compound of Formula (I), (II),(III), or (IV) described herein is co-administered in combination withtemozolomide and radiotherapy.

The compounds of Formula (I), (II), (III), or (IV) described herein canalso be co-administered with conventional hormonal therapeutic agentsincluding, but not limited to, steroids (e.g., dexamethasone),finasteride, aromatase inhibitors, tamoxifen, and gonadotropin-releasinghormone agonists (GnRH) such as goserelin.

Additionally, the compounds of Formula (I), (II), (III), or (IV)described herein can be co-administered with conventionalimmunotherapeutic agents including, but not limited to, immunostimulants(e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2,alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20,anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies),immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicinconjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate,etc.), and radioimmunotherapy (e.g., anti-CD20 monoclonal antibodyconjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I, etc.).

In further embodiments, the compounds of Formula (I), (II), (III), or(IV) described herein can also be co-administered with STAT 3inhibitors, Janus Kinase inhibitors, or EGFR inhibitors.

The particular choice of compounds used will depend upon the diagnosisof the attending physicians and their judgment of the condition of thepatient and the appropriate treatment protocol. The compounds may beadministered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,depending upon the nature of the disease, disorder, or condition, thecondition of the patient, and the actual choice of compounds used. Thedetermination of the order of administration, and the number ofrepetitions of administration of each therapeutic agent during atreatment protocol, is well within the knowledge of the physician afterevaluation of the disease being treated and the condition of thepatient.

Therapeutically-effective dosages can vary when the drugs are used intreatment combinations. Methods for experimentally determiningtherapeutically-effective dosages of drugs and other agents for use incombination treatment regimens are described in the literature. Forexample, the use of metronomic dosing, i.e., providing more frequent,lower doses in order to minimize toxic side effects, has been describedextensively in the literature Combination treatment further includesperiodic treatments that start and stop at various times to assist withthe clinical management of the patient.

For combination therapies described herein, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein may be administered either simultaneously with the biologicallyactive agent(s), or sequentially. If administered sequentially, theattending physician will decide on the appropriate sequence ofadministering protein in combination with the biologically activeagent(s).

In any case, the multiple therapeutic agents (one of which is a compoundof Formula (I), (II), (III), or (IV) described herein) may beadministered in any order or even simultaneously. If simultaneously, themultiple therapeutic agents may be provided in a single, unified form,or in multiple forms (by way of example only, either as a single pill oras two separate pills). One of the therapeutic agents may be given inmultiple doses, or both may be given as multiple doses. If notsimultaneous, the timing between the multiple doses may vary from morethan zero weeks to less than four weeks. In addition, the combinationmethods, compositions and formulations are not to be limited to the useof only two agents; the use of multiple therapeutic combinations arealso envisioned.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, can be modifiedin accordance with a variety of factors. These factors include thedisorder or condition from which the subject suffers, as well as theage, weight, sex, diet, and medical condition of the subject. Thus, thedosage regimen actually employed can vary widely and therefore candeviate from the dosage regimens set forth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein may be a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy may also beadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen may call for sequential administrationof the active agents or spaced-apart administration of the separateactive agents. The time period between the multiple administration stepsmay range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. Circadian variation of the target moleculeconcentration may also determine the optimal dose interval.

In addition, the compounds described herein also may be used incombination with procedures that may provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of a compound disclosedherein and/or combinations with other therapeutics are combined withgenetic testing to determine whether that individual is a carrier of amutant gene that is known to be correlated with certain diseases orconditions.

The compounds described herein and combination therapies can beadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound can vary. Thus, for example, the compounds can be used as aprophylactic and can be administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. The compounds and compositionscan be administered to a subject during or as soon as possible after theonset of the symptoms. The administration of the compounds can beinitiated within the first 48 hours of the onset of the symptoms,preferably within the first 48 hours of the onset of the symptoms, morepreferably within the first 6 hours of the onset of the symptoms, andmost preferably within 3 hours of the onset of the symptoms. The initialadministration can be via any route practical, such as, for example, anintravenous injection, a bolus injection, infusion over about 5 minutesto about 5 hours, a pill, a capsule, transdermal patch, buccal delivery,and the like, or combination thereof. A compound is preferablyadministered as soon as is practicable after the onset of a disease orcondition is detected or suspected, and for a length of time necessaryfor the treatment of the disease, such as, for example, from 1 day toabout 3 months. The length of treatment can vary for each subject, andthe length can be determined using the known criteria. For example, thecompound or a formulation containing the compound can be administeredfor at least 2 weeks, preferably about 1 month to about 5 years.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. Such kits can includea carrier, package, or container that is compartmentalized to receiveone or more containers such as vials, tubes, and the like, each of thecontainer(s) including one of the separate elements to be used in amethod described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. The containers can be formedfrom a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical productsinclude, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, bottles, and any packaging material suitable for aselected formulation and intended mode of administration and treatment.A wide array of formulations of the compounds and compositions providedherein are contemplated as are a variety of treatments for any disease,disorder, or condition that would benefit by inhibition of Olig2activity.

For example, the container(s) can include one or more compoundsdescribed herein, optionally in a composition or in combination withanother agent as disclosed herein. The container(s) optionally have asterile access port (for example the container can be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

A kit will typically may include one or more additional containers, eachwith one or more of various materials (such as reagents, optionally inconcentrated form, and/or devices) desirable from a commercial and userstandpoint for use of a compound described herein. Non-limiting examplesof such materials include, but not limited to, buffers, diluents,filters, needles, syringes; carrier, package, container, vial and/ortube labels listing contents and/or instructions for use, and packageinserts with instructions for use. A set of instructions will alsotypically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself, a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

In certain embodiments, the pharmaceutical compositions can be presentedin a pack or dispenser device which can contain one or more unit dosageforms containing a compound provided herein. The pack can for examplecontain metal or plastic foil, such as a blister pack. The pack ordispenser device can be accompanied by instructions for administration.The pack or dispenser can also be accompanied with a notice associatedwith the container in form prescribed by a governmental agencyregulating the manufacture, use, or sale of pharmaceuticals, whichnotice is reflective of approval by the agency of the form of the drugfor human or veterinary administration. Such notice, for example, can bethe labeling approved by the U.S. Food and Drug Administration forprescription drugs, or the approved product insert. Compositionscontaining a compound provided herein formulated in a compatiblepharmaceutical carrier can also be prepared, placed in an appropriatecontainer, and labeled for treatment of an indicated condition.

EXAMPLES

These examples are provided for illustrative purposes only and not tolimit the scope of the claims provided herein. The starting materialsand reagents used for the synthesis of the compounds described hereinmay be synthesized or can be obtained from commercial sources, such as,but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and FischerScientific.

HPLC methods: Platform (Method 1): Column—Zorbax Eclipse Plus C18, size2.1×50 mm; Solvent A: 0.10% formic acid in water, Solvent B: 0.00%formic acid in acetonitrile; Flow rate—0.7 mL/min; Gradient: 5% B to 95%B in 5 min and hold at 95% B for 2 min; UV detector—channel 1=254 nm,channel 2=254 nm.

Example 1: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(3)

Step 1: 2-Isocyanatonaphthalene (1)

A stirred mixture of 2-naphthylamine (1 g, 7.0 mmol), dichloromethane(DCM, 70 mL) and saturated sodium bicarbonate (NaHCO₃, 70 mL) at 0° C.was treated dropwise with triphosgene (0.77 g, 2.6 mmol). The mixturewas maintained at 0° C. for 75 minutes at which time TLC indicatedconsumption of starting material. The organic layer was separated anddried over sodium sulfate. After filtration the organics wereconcentrated to an oil which solidified on standing to afford the titlecompound (1) (1.2 g, 100%). This material was used directly in the nextstep.

Step 2: 1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea (2)

A mixture of 2-isocyanatonaphthalene (1) (1.2 g, 7.3 mmol) and2-amino-4-chloro-6-methylpyrimidine (0.95 g, 6.6 mmol) and toluene (8.8mL) was heated at 100° C. overnight. The mixture was cooled and dilutedwith MeOH (50.0 mL). The precipitates formed were filtered to afford thetitle compound (2) (1.3 g, 61%). LC/MS: Rt=0.27 min, m/z=313.1 [MH⁺].

Step 3:1-(4-((3-(Dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(3)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea (2) (75 mg,0.23 mmol) was suspended in 2-propanol (0.48 mL). To this was addedtriethylamine (0.05 mL, 0.36 mmol) and thenN,N′-dimethyl-1,3-propanediamine (0.04 mL, 0.28 mmol), and the mixturewas heated at 80° C. with stirring overnight. Upon cooling, the mixturewas diluted with ethanol (3 mL) and the precipitate formed was filteredto give the title compound (3) (55 mg, 61%). LC/MS: Method 1: Rt=0.36min, m/z=379.3 [MH+].

The compounds of examples 2-19 were prepared according to similarprocedures described for Example 1:

Cpd Yield RT Example ID Structure (mass/%) (min) MH⁺ 2 4

 19 mg, 23 0.36 351.2 3 5

 17 mg, 21 0.35 337.2 4 6

 30 mg, 33 0.38 365.3 5 7

 33 mg, 38 0.35 366.2 6 8

 59 mg, 72 0.35 338.2 7 9

 20 mg, 22 0.35 379.3 8 10

 32 mg, 36 0.35 365.3 9 11

 6 mg, 6 0.36 405.3 10 12

 27 mg, 50 0.33 336.2 11 13

 11 mg, 27 1.98 382.2 12 14

 23 mg, 40 2.04 352.2 13 15

 27 mg, 43 1.85 399.2 14 16

 35 mg, 53 1.74 413.3 15 17

 21 mg, 22 1.44 393.3 16 18

 62 mg, 71 1.71 368.2 17 19

 54 mg, 70 2.14 322.2 18 20

 60 mg, 81 2.09 308.2 19 21

115 mg, 53 0.26 322.2

Example 20: Synthesis of1-(4-((2-(1H-imidazol-2-yl)ethyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(22)

1-(4-((2-(1H-Imidazol-2-yl)ethyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(22) was prepared by a similar procedure as for example 1 using3-(1H-imidazol-2-yl)-ethylamine dihydrochloride except the final productwas purified by preparative TLC using 20% 1M NH₄OH in MeOH/80% DCM.(13.0 mg, 21%). LC/MS: Rt=1.62 min, m/z=388.2 [MH⁺].

Example 21: Synthesis of1-(4-((3-(1H-imidazol-2-yl)propyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(23)

1-(4-((3-(1H-Imidazol-2-yl)propyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(23) was prepared by a similar procedure as for example 16 using3-(1H-imidazol-2-yl)propan-1-amine dihydrochloride. Yield: (9.0 mg,14%). LC/MS: Rt=1.69 min, m/z=402.3 [MH⁺].

Example 22: Synthesis of1-(4-((2-(1H-pyrrol-2-yl)ethyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(24)

1-(4-((2-(1H-Pyrrol-2-yl)ethyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(24) was prepared by a similar procedure as for example 1 using2-pyrrol-2-ylethylamine except the final product was purified bypreparative TLC using 5% MeOH in DCM. (15.0 mg, 24%). LC/MS: Rt=2.64min, m/z=388.2 [MH+].

Example 23: Synthesis of methyl3-((6-methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)propanoate(25)

Methyl3-((6-methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)propanoate(25) was prepared by a similar procedure as for example 16 using methyl3-aminopropanoate hydrochloride. Yield: (7.0 mg, 11%). LC/MS: Rt=2.33min, m/z=380.2 [MH⁺].

Example 24: Synthesis of3-((6-methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)propanamide(26)

3-((6-Methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)propanamide(26) was prepared by a similar procedure as for example 1 using3-aminopropanamide hydrochloride except the final product was purifiedby preparative TLC using 10% 1M NH₄OH in MeOH/90% DCM. (6.0 mg, 7%).LC/MS: Rt=1.89 min, m/z=365.2 [MH⁺].

Example 25: Synthesis of1-(4-((2,2-difluoro-3-hydroxypropyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(27)

1-(4-((2,2-Difluoro-3-hydroxypropyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(27) was prepared by a similar procedure as for example 1 using3-amino-2,2-difluoropropan-1-ol except the final product was purified bypreparative TLC using 95/5 DCM/MeOH. (4.0 mg, 4%). LC/MS: Rt=2.22 min,m/z=388.2 [MH+].

Example 26: Synthesis of1-(4-((2-(2-(dimethylamino)ethoxy)ethyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(28)

1-(4-((2-(2-(Dimethylamino)ethoxy)ethyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(28) was prepared by a similar procedure as for example 23 using2-(2-dimethylamino-ethoxy)-ethylamine. Yield: (8.0 mg, 8%). LC/MS:Rt=1.52 min, m/z=409.3 [MH+].

Example 27: Synthesis of1-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)-3-(naphthalen-2-yl)urea(30)

Step 1: tert-Butylmethyl(2-((6-methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)ethyl)carbamate(29)

A mixture of 1-(4-chloro-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(2) (75 mg, 0.24 mmol), N-(2-aminoethyl)-N-methyl carbamic acidtert-butyl ester (50 mg, 0.29 mmol), and triethylamine (0.05 mL, 0.36mmol) was heated to reflux with stirring in 2-propanol (0.48 mL)overnight. Upon cooling methanol (3 mL) was added and after 30 minutes,the precipitate formed was filtered to give the title compound (29) (77mg, 70%). This material was used directly in the next step.

Step 2:1-(4-Methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)-3-(naphthalen-2-yl)urea(30)

The BOC derivative (29) (74 mg, 0.16 mmol) was suspended in DCM (0.12mL) to which trifluoroacetic acid (0.12 mL, 1.5 mmol) was added. Thereaction mixture was stirred for 2 hours before addition of moretrifluoroacetic acid (0.15 mL). This mixture was warmed to 45° C. andstirred overnight. Saturated NaHCO₃ solution was added and the mixturewas stirred for 30 minutes. The precipitate was filtered and washed withwater to obtain the desired compound as a white solid (30) (51 mg, 88%).LC/MS: Rt=0.37 min, m/z=351.2 [MH⁺].

Example 28: Synthesis of1-(4-methyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)-3-(naphthalen-2-yl)urea(31)

1-(4-Methyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)-3-(naphthalen-2-yl)ureawas prepared by a similar procedure as for example 26 using tert-butyl(3-aminopropyl)(methyl)carbamate except the final product was purifiedby preparative TLC using 40% 1M NH₄OH in MeOH/60% DCM. Yield: (8.3 mg,31%). LC/MS: Rt=1.48 min, m/z=365.3 [MH+].

Example 29: Synthesis of1-(4-methyl-6-((piperidin-3-ylmethyl)amino)pyrimidin-2-yl)-3-(naphthalen-2-yl)urea(32)

1-(4-Methyl-6-((piperidin-3-ylmethyl)amino)pyrimidin-2-yl)-3-(naphthalen-2-yl)ureawas prepared by a similar procedure as for example 26 using tert-butyl3-(aminomethyl)piperidine-1-carboxylate except the final product waspurified by preparative TLC using 10% 1M NH₄OH in MeOH/90% DCM. Yield:(21.2 mg, 31%). LC/MS: Rt=1.59 min, m/z=391.3 [MH+].

Example 30: Synthesis of1-(4-methyl-6-((4-(methylamino)butyl)amino)pyrimidin-2-yl)-3-(naphthalen-2-yl)urea(33)

1-(4-Methyl-6-((4-(methylamino)butyl)amino)pyrimidin-2-yl)-3-(naphthalen-2-yl)ureawas prepared by a similar procedure as for example 26 using tert-butyl(3-aminobutyl)(methyl)carbamate except the final product was purified bypreparative TLC using 40% 1M NH₄OH in MeOH/60% DCM. Yield: (16.8 mg,30%). LC/MS: Rt=0.35 min, m/z=379.3 [MH+].

Example 31: Synthesis ofN-(3-((6-methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)propyl)acetamide(34)

A mixture of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(Example 2, compound 4) (75 mg, 0.21 mmol), acetic anhydride (0.02 mL,0.24 mmol), pyridine (0.11 mL, 1.3 mmol) and a catalytic amount ofN,N-dimethylaminopyridine in DCM (0.54 mL) was stirred at roomtemperature for 3 hours. At this time the mixture was cooled to −20° C.before dilution with MeOH (5 mL). The resulting solids were filtered anddried to yield the title product (34) (42 mg, 50%). LC/MS: Rt=2.05 min,m/z=393.3 [MH+].

Example 32: Synthesis ofN-(2-((6-methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)ethyl)acetamide(35)

N-(2-((6-Methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)ethyl)acetamidewas prepared by a similar procedure as for example 26 from1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(Example 2, compound 5). Yield: (67.0 mg, 79%). LC/MS: Rt=1.85 min,m/z=379.2 [MH+].

Example 33: Synthesis ofN-(2-((6-methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)ethyl)methanesulfonamide(36)

To a mixture of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(Example 2, compound 5), (75 mg, 0.22 mmol) and triethylamine (0.06 mL,0.45 mmol) in DCM (0.30 mL) that was cooled to 0° C. was added,methanesulfonyl chloride (0.02 mL, 0.25 mmol), and this was stirred atroom temperature for 2 hours. The mixture was then cooled in a freezer(−20° C.), then diluted with MeOH (5 mL) and the resulting solidsfiltered. This material was purified by preparative TLC using 5% MeOH inDCM as eluent to give the title product (36) (8 mg, 9%). LC/MS: Rt=2.06min, m/z=415.2 [MH+].

Example 34: Synthesis ofN-(3-((6-methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)propyl)methanesulfonamide(37)

N-(3-((6-Methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)propyl)methanesulfonamidewas prepared by a similar procedure as for example 32 from1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(Example 2, 4). Yield: (5.2 mg, 6%). LC/MS: Rt=2.08 min, m/z=429.2[MH+].

Example 35: Synthesis of2,2,2-trifluoro-N-(2-((6-methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)ethyl)acetamide(38)

To a mixture of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(Example 2, compound 5), (89 mg, 0.26 mmol) and triethylamine (0.04 mL,0.28 mmol) in DCM (0.50 mL) that was cooled to 0° C. was added,trifluoroacetic acid anhydride (0.02 mL, 0.25 mmol), and this wasstirred at room temperature for 1 hour. At this time, the mixture wasdiluted with MeOH (2 mL) and the resulting solids filtered to give thetitle product (38) (87.1 mg, 76%). LC/MS: Rt=2.51 min, m/z=433.0 [MH+].

Example 36: Synthesis ofN,N-dimethyl-3-((6-methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)propanamide(42)

Step 1: Benzyl (3-(dimethylamino)-3-oxopropyl)carbamate (40)

3-(((Benzyloxy)carbonyl)amino)propanoic acid (1.5 g, 6.6 mmol) wasdissolved in DMF and to this solution was added 40% aqueous dimethylamine (2.4 mL), 1-hydroxybenzotriazole hydrate (3.63 g, 24 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.15 g, 27mmol). The resulting mixture was stirred for 24 hours. At this time themixture was partitioned between ethyl acetate and 0.1N hydrochloric acidsolution. The organic layer was washed twice with saturated aqueoussodium bicarbonate and once with brine before separation and drying overanhydrous sodium sulfate. The filtrate was evaporated to yield theproduct which was used directly. Yield: (1.57 g, 95%).

Step 2: 3-Amino-N,N-dimethylpropanamide (41)

Benzyl (3-(dimethylamino)-3-oxopropyl)carbamate (40) (1.57 g, 6.3 mmol)was dissolved in ethanol (12 mL) and ethyl acetate (12 mL) and to thiswas added palladium (10% activated on carbon: 0.1 g). The vessel wascharged with hydrogen at 1 atmosphere and the mixture stirred for 16hours. The mixture was filtered through celite and the solventsevaporated to yield a clear oil (0.73 g, 100%) that was used directly inthe next step.

Step 3:N,N-dimethyl-3-((6-methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)propanamide(42)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea (2) (100 mg,0.32 mmol) was mixed with 2-propanol (3 mL), triethylamine (0.07 mL,0.48 mmol) and 3-amino-N,N-dimethylpropanamide (41) (74 mg, 0.64 mmol)and the mixture was stirred vigorously at 80° C. overnight. On cooling,the solids were filtered and washed with ethanol to yield the titleproduct (42) (91 mg, 73%). LC/MS: Rt=2.01 min, m/z=393.3 [MH+].

Example 37: Synthesis ofN-methyl-3-((6-methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)propanamide(43)

N-Methyl-3-((6-methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)propanamidewas prepared by a similar procedure as for example 36 from1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(Example 2, compound 4) and 40% aqueous methylamine. Yield: (33 mg,52%). LC/MS: Rt=1.98 min, m/z=379.2 [MH+].

Example 38: Synthesis of1-(4-(methoxyamino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea (44)

N-Methyl-3-((6-methyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)propanamidewas prepared by a similar procedure as for example 1 from1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(Example 2, compound 4) and O-methyl hydroxylamine hydrochloride. Yield:(33 mg, 30%). LC/MS: Rt=3.17 min, m/z=324.2 [MH+].

Example 39: Synthesis of1-(4-(hydroxyamino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea (45)

1-(4-(Hydroxyamino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea wasprepared by a similar procedure as for example 1 from1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(Example 2, 4) and hydroxylamine hydrochloride. The title product waspurified by column chromatography in a gradient of 0-15% 1N NH₄OH inMeOH in DCM. Yield: (15 mg, 20%). LC/MS: Rt=2.00 min, m/z=310.2 [MH+].

Example 40: Synthesis of1-(4-amino-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea (47)

Step 1:1-(4-((4-Methoxybenzyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(46)

1-(4-((4-Methoxybenzyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)ureawas prepared by a similar procedure as for example 1 from1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(Example 2, 4) and 4-methoxybenzylamine. This material was used directlyin the next step.

Step 2: 1-(4-Amino-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea (47)

1-(4-((4-Methoxybenzyl)amino)-6-methylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(46) was dissolved in DCM (0.07 mL) and treated with trifluoroaceticacid (0.07 mL). After stirring for 2 hours, the mixture was heated firstat 40° C. for 20 hrs and then at 72° C. for 21 hrs. Additionaltrifluoroacetic acid (0.5 mL) was added and heating continued at 80° C.After 4 hrs, the mixture was partitioned with DCM (2 mL) and saturatedsodium bicarbonate solution (2 mL) and the aqueous layer wasre-extracted with DCM (2×2 mL). The combined organic fractions weredried and the residue obtained purified by column chromatography elutingfirst with ethyl acetate/hexanes (50/50) followed by a gradient of 0-30%MeOH in DCM. Purification afforded the title product. Yield: (4.8 mg,18%). LC/MS: Rt=2.31 min, m/z=294.1 [MH+].

Example 41: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea(50)

Step 1: Isoquinoline-6-carbonyl Azide (48)

To a solution of quinoline-6-carboxylic acid (1 g, 5.7 mmol) inanhydrous DMF (10 mL) was added trimethylamine (0.96 mL, 6.8 mmol)followed by diphenyl phosphoryl azide (1.48 mL, 6.8 mmol) and thismixture was stirred overnight. At this time the resulting solution wasdiluted with ethyl acetate and washed repeatedly with water. The organiclayer was separated and dried over sodium sulfate. After filtration theorganics were concentrated and the residue purified by silica gelchromatography eluting with a gradient of 0-45% ethyl acetate inhexanes. The title compound was obtained as a white solid followingevaporation of fractions (1.0 g, 85%). This material was used directlyin the next step.

Step 2: 1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea(49)

A mixture of isoquinoline-6-carbonyl azide (48) (1.2 g, 4.8 mmol and2-amino-4-chloro-6-methylpyrimidine (0.70 g, 4.8 mmol) in toluene (50mL) was treated with N,N-diisopropylethylamine (1.3 mL, 7.2 mmol) andthe mixture heated at 110° C. for 2 hours. The mixture was cooled andthe solvents evaporated to give a residue that was purified by flashchromatography with a gradient of 0-5% MeOH in DCM. Evaporation of therelevant fractions gave the title compound (49) (0.73 g, 46%). LC/MS:Rt=1.35 min, m/z=314.1 [MH⁺].

Step 3:1-(4-((3-(Dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea(50)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea (49) (50mg, 0.15 mmol) was suspended in 2-propanol (1 mL). To this was addedtriethylamine (0.03 mL, 0.23 mmol) and thenN,N′-dimethyl-1,3-propanediamine (0.02 mL, 0.18 mmol), and the mixturewas heated at 80° C. with stirring overnight. Upon cooling the mixturewas purified by preparative TLC in 5-20% 3M methanolic ammoniumhydroxide in DCM to give the title compound (50) (35 mg, 58%). LC/MS:Rt=0.57 min, m/z=380.3 [MH+].

Example 42: Synthesis of1-(4-((2-(dimethylamino)ethyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea(51)

1-(4-((2-(Dimethylamino)ethyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)ureawas prepared by a similar procedure as for example 40 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea (Example41, compound 49) and N,N-dimethylethylenediamine. Yield: (42 mg, 72%).LC/MS: Rt=0.58 min, m/z=366.2 [MH+].

Example 43: Synthesis of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea(52)

1-(4-((2-Aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea(52) was prepared by a similar procedure as for example 40 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea (Example41, compound 49) and ethylenediamine except the product was purified byflash chromatography in a gradient of 0-45% 3M methanolic ammoniumhydroxide in DCM. Yield: (168 mg, 78%). LC/MS: Rt=0.64 min, m/z=338.2[MH+].

Example 44: Synthesis of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea(53)

1-(4-((3-Aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea(53) was prepared by a similar procedure as for example 40 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea (Example41, compound 49) and 1,3-diaminopropane with the exception that thereaction mixture was filtered and washed with EtOH/Et₂O (1/1) to affordthe title product. Yield: (178 mg, 79%). LC/MS: Rt=0.56 min, m/z=352.2[MH+].

The compounds of examples 45-50 were prepared according to similarprocedures described for Example 44:

Cpd Yield RT Example ID Structure (mass/%) (min) MH⁺ 45 54

25 mg, 44 0.97 323.0 46 55

38 mg, 81 0.81 309.2 47 56

32 mg, 57 1.34 351.2 48 57

34 mg, 61 1.27 353.2 49 58

33 mg, 57 0.65 366.2 50 59

29 mg, 48 0.90 380.2

Example 51: Synthesis of1-(4-((2-hydroxyethyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea(60)

1-(4-((2-Hydroxyethyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea(60) was prepared by a similar procedure as for example 43 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea (Example41, compound 49) and ethanolamine except the product was purified byflash chromatography in a gradient of 0-30% 3M methanolic ammoniumhydroxide in DCM. Yield: (16 mg, 30%). LC/MS: Rt=0.78 min, m/z=339.2[MH+].

Example 52: Synthesis of1-(isoquinolin-6-yl)-3-(4-(methoxyamino)-6-methylpyrimidin-2-yl)urea(61)

1-(Isoquinolin-6-yl)-3-(4-(methoxyamino)-6-methylpyrimidin-2-yl)urea(61) was prepared by a similar procedure as for example 43 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea (Example41, 49) and O-methylhydroxylamine hydrochloride, except the product waspurified by flash chromatography in 20% MeOH in DCM. Yield: (22 mg,20%). LC/MS: Rt=1.48 min, m/z=325.2 [MH+].

Example 53: Synthesis of1-(4-(hydroxyamino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea(62)

1-(4-(Hydroxyamino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea wasprepared by a similar procedure as for example 44 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea (Example41, compound 49) and hydroxylamine hydrochloride, except the solidsobtained were partitioned between DCM and saturated NaHCO₃. The organiclayer was dried over anhydrous sodium sulfate, filtered and evaporatedto afford the title product (62) (22.5 mg, 30%). LC/MS: Rt=1.21 min,m/z=311.1 [MH+].

Example 54: Synthesis of1-(isoquinolin-6-yl)-3-(4-methyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)urea(64)

Step 1: tert-Butyl(3-((2-(3-(isoquinolin-6-yl)ureido)-6-methylpyrimidin-4-yl)amino)propyl)(methyl)carbamate(63)

A mixture of1-(4-chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea (Example41, compound 49) (100 mg, 0.30 mmol), N-(3-aminopropyl)-N-methylcarbamic acid tert-butyl ester (71 mg, 0.36 mmol), and triethylamine(0.06 mL, 0.45 mmol) was heated to 90° C. with stirring in 2-propanol (3mL) overnight. Upon cooling solvent was evaporated and the residuepurified by column chromatography in a gradient of 0-10% 3M methanolicammonium hydroxide in DCM to afford the title product (63). (140 mg,94%). This material was used directly in the next step.

Step 2:1-(Isoquinolin-6-yl)-3-(4-methyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)urea(64)

The BOC derivative (63) (140 mg, 0.29 mmol) was suspended in DCM (2.8mL) to which trifluoroacetic acid (0.22 mL, 2.9 mmol) was added. Thereaction mixture was stirred for 2 hours before addition of moretrifluoroacetic acid (0.29 mL). This mixture was warmed to 45° C. andstirred overnight. Saturated NaHCO₃ solution was added. Ethanol wasadded and the precipitate was filtered. This material was purified byflash chromatography in a gradient of 0-20% 3M methanolic ammoniumhydroxide in DCM to afford the title product (64) (24 mg, 22%). LC/MS:Rt=0.65 min, m/z=366.3 [MH+].

Example 55: Synthesis of1-(isoquinolin-6-yl)-3-(4-methyl-6-((4-(methylamino)butyl)amino)pyrimidin-2-yl)urea(65)

1-(Isoquinolin-6-yl)-3-(4-methyl-6-((4-(methylamino)butyl)amino)pyrimidin-2-yl)urea(65) was prepared by a similar procedure as for example 54 usingtert-butyl (3-aminobutyl)(methyl)carbamate except the final product wasextracted into DCM. Drying and evaporation of the solvent afforded thetitle product (11.5 mg, 9%). LC/MS: Rt=0.69 min, m/z=380.3 [MH+].

Example 56: Synthesis ofN-(3-((2-(3-(isoquinolin-6-yl)ureido)-6-methylpyrimidin-4-yl)amino)propyl)acetamide(66)

A mixture of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea(Example 43, compound 52) (50 mg, 0.14 mmol), acetic anhydride (0.01 mL,0.15 mmol), pyridine (0.07 mL, 0.83 mmol) and a catalytic amount ofN,N-dimethylaminopyridine in DCM (1 mL) was stirred at 60° C. for 2hours. At this time the mixture was concentrated and the residuepurified by flash chromatography in 0-30% MeOH in DCM and thepreparative TLC in 5-10% 3M methanolic ammonium hydroxide in DCM toafford the title product (66) (27 mg, 48%). LC/MS: Rt=0.83 min,m/z=394.1 [MH+].

Example 57: Synthesis ofN-(2-((2-(3-(isoquinolin-6-yl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)acetamide(67)

N-(2-((2-(3-(Isoquinolin-6-yl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)acetamide(67) was prepared by a similar procedure as for example 56 from1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea(Example 43, compound 52). Yield: (13.0 mg, 23%). LC/MS: Rt=0.78 min,m/z=380.2 [MH+].

Example 58: Synthesis ofN-(3-((2-(3-(isoquinolin-6-yl)ureido)-6-methylpyrimidin-4-yl)amino)propyl)methanesulfonamide(71)

Step 1: tert-Butyl (3-(methylsulfonamido)propyl)carbamate (69)

To a solution of tert-butyl-3-aminopropyl-carbamate (68) (1.07 g, 5.8mmol) in anhydrous THF (15 mL) was added triethylamine (1.2 mL, 8.7mmol) and the mixture was cooled to 0° C. Methane sulfonyl chloride(0.64 mL, 8.2 mmol) was added and the mixture was stirred at 0° C. for1.5 h. The solvent was removed under reduced pressure, and the resultingresidue was diluted with EtOAc and washed with water. The aqueous layerwas back-extracted with EtOAc three times. The organic layers werecombined and washed with saturated brine, and dried over sodium sulfateand filtered. The solvent was evaporated to obtain the title compound(69) (1.45 g, 95%) as a solid which was used directly.

Step 2: N-(3-Aminopropyl)methanesulfonamide hydrochloride (70)

tert-Butyl (3-(methylsulfonamido)propyl)carbamate (69) (1.45 g, 5.5mmol) was dissolved in 4M HCl in dioxane (18 mL) and stirred at roomtemperature. The reaction was monitored by TLC until starting materialwas consumed. At this point solvent was evaporated and the residue useddirectly. Yield: (1.01 g, 93%)

Step 3:N-(3-((2-(3-(Isoquinolin-6-yl)ureido)-6-methylpyrimidin-4-yl)amino)propyl)methanesulfonamide(71)

To a mixture of1-(4-chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea (Example41, 49) (100 mg, 0.30 mmol) and N-(3-aminopropyl)methanesulfonamidehydrochloride (70) (180 mg, 0.90 mmol) in 2-propanol (3 mL) was addedtriethylamine (0.21 mL, 1.5 mmol) and this was heated at 90° C.overnight. The solids were filtered, washed with ethanol and dried toyield the title product (71) (105 mg, 77%). LC/MS: Rt=1.25 min,m/z=430.2 [MH+].

Example 59: Synthesis ofN-(2-((2-(3-(isoquinolin-6-yl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)methanesulfonamide(75)

Step 1: tert-Butyl (2-(methylsulfonamido)ethyl)carbamate (73)

To a solution of tert-butyl-2-aminoethyl-carbamate (72) (10 g, 61 mmol)in anhydrous THF (200 mL) was added triethylamine (12.9 mL, 91.8 mmol)and the mixture was cooled to 0° C. Methane sulfonyl chloride (6.7 mL,85.6 mmol) was added and the mixture was stirred at 0° C. for 1.5 h. Thesolvent was removed under reduced pressure, and the resulting residuewas diluted with EtOAc and washed with water. The aqueous layer wasback-extracted with EtOAc three times. The organic layers were combinedand washed with saturated brine, and dried over sodium sulfate andfiltered. The solvent was evaporated to obtain the title compound (73)as a yellow solid (12.9 g, 84%) which was used directly.

Step 2: N-(2-Aminoethyl)methanesulfonamide hydrochloride (74)

tert-Butyl (2-(methylsulfonamido)ethyl)carbamate (73) (12.9 g, 51.5mmol) was dissolved in 4M HCl in dioxane (170 mL) and stirred at roomtemperature. The reaction was monitored by TLC until starting materialwas consumed. At this point solvent was evaporated and the residue useddirectly.

Step 3:N-(2-((2-(3-(Isoquinolin-6-yl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)methanesulfonamide(75)

To a mixture of1-(4-chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea (Example41, compound 49) (50 mg, 0.15 mmol) andN-(2-aminoethyl)methanesulfonamide hydrochloride (74) (42 mg, 0.23 mmol)in 2-propanol (1 mL) was added triethylamine (0.06 mL, 0.45 mmol) andthis was heated at 90° C. overnight. The mixture was concentrated andthe residue purified by flash chromatography using a gradient of 0-20%MeOH in DCM to yield the title product (75) (27 mg, 40%). LC/MS: Rt=0.88min, m/z=416.2 [MH+].

Example 60: Synthesis of3-((2-(3-(isoquinolin-6-yl)ureido)-6-methylpyrimidin-4-yl)amino)-N,N-dimethylpropanamide(76)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea (Example41, compound 49) (100 mg, 0.32 mmol) was mixed with 2-propanol (3 mL),triethylamine (0.07 mL, 0.48 mmol) and 3-amino-N,N-dimethylpropanamide(41) (74 mg, 0.64 mmol) and the mixture was stirred vigorously at 80° C.overnight. On cooling, the solids were filtered and washed with ethanolto yield the title product (76) (100 mg, 76%). LC/MS: Rt=0.92 min,m/z=394.2 [MH+].

Example 61: Synthesis of3-((2-(3-(isoquinolin-6-yl)ureido)-6-methylpyrimidin-4-yl)amino)-N-methylpropanamide(77)

3-((2-(3-(isoquinolin-6-yl)ureido)-6-methylpyrimidin-4-yl)amino)-N-methylpropanamide(77) was prepared by a similar procedure as for example 37 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-6-yl)urea (Example41, compound 49). Yield: (25 mg, 39%). LC/MS: Rt=0.79 min, m/z=380.2[MH+].

Example 62: Synthesis of1-(benzofuran-5-yl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(80)

Step 1: 1-(Benzofuran-5-yl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea (79)

To a solution of 4-aminobenzofuran (78) (0.5 g, 3.6 mmol) in DCM (35 mL)was added triethylamine (0.77 mL, 5.5 mmol) and the mixture was cooledto 0° C. Triphosgene (1.1 g, 3.6 mmol) was added in several portions tothe mixture at 0° C. The ice bath was removed and the mixture allowed towarm to room temperature before stirring for an additional 5 hours.Concentration in vacuo yielded a solid which was diluted with toluene(30 mL) and to this was added 2-amino-4-chloro-6-methylpyrimidine (0.49g, 3.3 mmol) in one portion. The resulting mixture was heated to refluxat 100° C. overnight. The reaction was diluted with Et₂O and filtered toafford a pale pink solid. This material was purified by flashchromatography (gradient elution, 0-45% EtOAc/hexanes), followed byrecrystallization of the major fraction in MeOH/DCM/hexanes to give thetitle compound (79) as a white solid (0.42 g, 36%). LC/MS: Rt=3.27 min,m/z=303.1 [MH+].

Step 2:1-(benzofuran-5-yl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(80)

1-(Benzofuran-5-yl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea (79) (50 mg,0.16 mmol) was suspended in 2-propanol (1 mL). To this was addedtriethylamine (0.03 mL, 0.24 mmol) and thenN,N′-dimethyl-1,3-propanediamine (0.02 mL, 0.19 mmol), and the mixturewas heated at 90° C. with stirring overnight. Upon cooling the mixturewas concentrated and the residue purified by preparative TLC elutingwith 5% 3M methanolic ammonia in DCM to give the title compound (80) (40mg, 66%). LC/MS: Method 1: Rt=1.15 min, m/z=379.3 [MH+].

Example 63: Synthesis of1-(benzofuran-5-yl)-3-(4-((2-(dimethylamino)ethyl)amino)-6-methylpyrimidin-2-yl)urea(81)

1-(Benzofuran-5-yl)-3-(4-((2-(dimethylamino)ethyl)amino)-6-methylpyrimidin-2-yl)urea(81) was prepared by a similar procedure as for example 62 from1-(benzofuran-5-yl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea (Example 62,compound 79). Yield: (25 mg, 39%). LC/MS: Rt=0.79 min, m/z=380.2 [MH+].

Example 64: Synthesis of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(benzofuran-5-yl)urea(82)

1-(Benzofuran-5-yl)-3-(4-((2-(dimethylamino)ethyl)amino)-6-methylpyrimidin-2-yl)urea(82) was prepared by a similar procedure as for example 62 from1-(benzofuran-5-yl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea (Example 62,compound 79) except the title product was purified by flashchromatography eluting with 0-45% 3M methanolic ammonia in DCM, thenre-purified by preparative TLC in 30% 3M methanolic ammonia in DCM.Yield: (30 mg, 28%). LC/MS: Rt=1.23 min, m/z=327.2 [MH+].

Example 65: Synthesis of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(benzofuran-5-yl)urea(83)

1-(4-((3-Aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(benzofuran-5-yl)ureawas (83) prepared by a similar procedure as for example 62 from1-(benzofuran-5-yl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea (Example 62,compound 79) except the title product was purified by flashchromatography eluting with 0-35% 3M methanolic ammonia in DCM, thenre-purified by preparative TLC in 20% 3M methanolic ammonia in DCM.Yield: (30 mg, 28%). LC/MS: Rt=1.10 min, m/z=341.2 [MH+].

Example 66: Synthesis ofN-(2-((2-(3-(benzofuran-5-yl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)acetamide(84)

A mixture of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(benzofuran-5-yl)urea(Example 64, compound 82) (50 mg, 0.15 mmol), acetic anhydride (0.02 mL,0.17 mmol), pyridine (1 mL, 0.83 mmol) and N,N-dimethylaminopyridine (5mg, 0.04 mmol) in DCM (0.1 mL) was stirred at 60° C. for 2 hours. Atthis time the mixture was concentrated and the residue purified by flashchromatography in 0-25% 3M methanolic ammonia in DCM and thenpreparative TLC in 5-10% MeOH in DCM to afford the title product (84)(18 mg, 32%). LC/MS: Rt=1.50 min, m/z=369.2 [MH+].

Example 67: Synthesis ofN-(3-((2-(3-(benzofuran-5-yl)ureido)-6-methylpyrimidin-4-yl)amino)propyl)acetamide(85)

N-(3-((2-(3-(benzofuran-5-yl)ureido)-6-methylpyrimidin-4-yl)amino)propyl)acetamide(85) was prepared by a similar procedure as for example 66 from1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(benzofuran-5-yl)urea(Example 65, compound 83). Yield: (32 mg, 28%). LC/MS: Rt=1.53 min,m/z=383.2 [MH+].

Example 68: Synthesis ofN-(2-((2-(3-(benzofuran-5-yl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)methanesulfonamide(86)

To a mixture of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(benzofuran-5-yl)urea(Example 64, compound 82), (50 mg, 0.15 mmol) in pyridine (1 mL) wasadded methanesulfonyl chloride (0.03 mL, 0.44 mmol), and this was heatedat 60° C. for 2 hours. At this time the mixture was concentrated andpurified by flash chromatography first in 0-5% MeOH in DCM and then0-25% 3M methanolic ammonia in DCM. This material was re-purified bypreparative TLC using 5-10% MeOH in DCM as eluent to give the titleproduct (86) (22 mg, 36%). LC/MS: Rt=1.63 min, m/z=405.2 [MH+].

Example 69: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-3-yl)urea(89)

Step 1: Isoquinoline-3-carbonyl Azide (87)

To a solution of isoquinoline-3-carboxylic acid (1 g, 5.7 mmol) inanhydrous DMF (10 mL) was added triethylamine (0.95 mL, 6.7 mmol)followed by diphenyl phosphoryl azide (1.46 mL, 6.7 mmol) and thismixture was stirred overnight. At this time the resulting solution wasdiluted with ethyl acetate and washed repeatedly with water. The organiclayer was separated and dried over sodium sulfate. After filtration theorganics were concentrated and the residue purified by silica gelchromatography eluting with a gradient of 0-45% ethyl acetate inhexanes. The title compound (87) was obtained (0.80 g, 69%) as a whitesolid following evaporation of fractions. This material was useddirectly in the next step.

Step 2: 1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-3-yl)urea(88)

A mixture of isoquinoline-3-carbonyl azide (87) (0.17 g, 0.83 mmol) and2-amino-4-chloro-6-methylpyrimidine (0.10 g, 0.69 mmol) in toluene (13mL) was treated with N,N-diisopropylethylamine (0.18 mL, 1.0 mmol) andthe mixture heated at 110° C. for 3 hours. The mixture was cooled andthe solvents evaporated to give a residue that was purified by flashchromatography with a gradient of 0-50% ethyl acetate in hexanes andthen preparative TLC using 50% ethyl acetate in hexanes. Evaporation ofthe relevant fractions gave the title compound (88) (0.11 g, 50%). Thismaterial was used directly in the next step.

Step 3:1-(4-((3-(Dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-3-yl)urea(89)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-3-yl)urea (88) (50mg, 0.15 mmol) was suspended in 2-propanol (1 mL). To this was addedtriethylamine (0.03 mL, 0.23 mmol) and thenN,N′-dimethyl-1,3-propanediamine (0.02 mL, 0.18 mmol), and the mixturewas heated at 80° C. with stirring overnight. Upon cooling the mixturewas purified by preparative TLC in 15% 3M methanolic ammonium hydroxidein DCM to give the title compound (89) (35 mg, 58%). LC/MS: Rt=1.22 min,m/z=380.2 [MH+].

Example 70: Synthesis of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-3-yl)urea(90)

1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-3-yl)urea(90) was prepared by a similar procedure as for example 69 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-3-yl)urea (88) (50mg, 0.15 mmol) with purification of the title compound by flashchromatography in 0-20% 3M methanolic ammonium hydroxide in DCM. Yield:(32 mg, 28%). LC/MS: Rt=1.17 min, m/z=338.2 [MH+].

Example 71: Synthesis of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-3-yl)urea(91)

1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-3-yl)urea(91) was prepared by a similar procedure as for example 69 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-3-yl)urea (88) (170mg, 0.52 mmol) except the reaction mixture was filtered upon cooling toafford the title product (50 mg, 26%). LC/MS: Rt=1.27 min, m/z=352.2[MH+].

Example 72: Synthesis ofN-(3-((2-(3-(isoquinolin-3-yl)ureido)-6-methylpyrimidin-4-yl)amino)propyl)acetamide(92)

A mixture of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-3-yl)urea(Example 71, compound 91) (45 mg, 0.13 mmol), acetic anhydride (0.01 mL,0.14 mmol), pyridine (0.06 mL, 0.79 mmol) and a catalytic amount ofN,N-dimethylaminopyridine in DCM (0.5 mL) was stirred at roomtemperature for 2 hours. At this time the mixture was cooled in afreezer before dilution with ether (5 mL). The solids were filtered andwashed with ether to afford the title product (92) on drying. (25 mg,50%). LC/MS: Rt=1.56 min, m/z=394.2 [MH+].

Example 73: Synthesis ofN-(2-((2-(3-(isoquinolin-3-yl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)methanesulfonamide(93)

To a mixture of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-3-yl)urea(Example 70, compound 90) (50 mg, 0.15 mmol) and triethylamine (0.03 mL,0.22 mmol) in DCM (0.30 mL) that was cooled to 0° C. was added,methanesulfonyl chloride (0.01 mL, 0.16 mmol), and this was stirred atroom temperature for 2 hours. At this time the mixture was diluted withDCM (5 mL) and the mixture purified by flash chromatography using 0-20%3M methanolic ammonia in DCM as eluent to give the title product (93)(30 mg, 49%). LC/MS: Rt=1.75 min, m/z=416.2 [MH+].

Example 74: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea(96)

Step 1: Quinoline-2-carbonyl Azide (94)

To a solution of quinoline-2-carboxylic acid (1 g, 5.7 mmol) inanhydrous DMF (10 mL) was added triethylamine (0.95 mL, 6.8 mmol)followed by diphenyl phosphoryl azide (1.48 mL, 6.8 mmol) and thismixture was stirred overnight. At this time the resulting solution wasdiluted with ethyl acetate and washed repeatedly with water. The organiclayer was washed with brine, separated and dried over sodium sulfate.After filtration the organics were concentrated and the residue purifiedby silica gel chromatography eluting with a gradient of 0-20% ethylacetate in hexanes. The title compound (94) was obtained as a whitesolid following evaporation of fractions (0.77 g, 65%). This materialwas used directly in the next step.

Step 2: 1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea (95)

A mixture of quinoline-2-carbonyl azide (94) (0.17 g, 0.83 mmol) and2-amino-4-chloro-6-methylpyrimidine (0.10 g, 0.69 mmol) in toluene (13mL) was treated with N,N-diisopropylethylamine (0.18 mL, 1.0 mmol) andthe mixture heated at 110° C. for 3 hours. The mixture was cooled andthe solvents evaporated to give a residue that was purified by flashchromatography with a gradient of 0-40% ethyl acetate in hexanes.Evaporation of the relevant fractions gave the title compound (95) (0.20g, 89%). This material was used directly in the next step.

Step 3:1-(4-((3-(Dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea(96)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea (95) (50 mg,0.15 mmol) was suspended in 2-propanol (1 mL). To this was addedtriethylamine (0.03 mL, 0.23 mmol) and thenN,N′-dimethyl-1,3-propanediamine (0.02 mL, 0.18 mmol), and the mixturewas heated at 80° C. with stirring overnight. Upon cooling the mixturewas purified by preparative TLC in 15% 3M methanolic ammonium hydroxidein DCM to give the title compound (96) (32 mg, 53%). LC/MS: Rt=1.22 min,m/z=380.2 [MH+].

Example 75: Synthesis of1-(4-((2-(dimethylamino)ethyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea(97)

1-(4-((2-(Dimethylamino)ethyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea(97) was prepared by a similar procedure as for example 74 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea (95) (50 mg,0.15 mmol) using 10% 1M methanolic ammonium hydroxide in DCM to yieldthe title compound. Yield: (35 mg, 40%). LC/MS: Rt=1.16 min, m/z=366.2[MH+].

Example 76: Synthesis of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea(98)

1-(4-((2-Aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea(98) was prepared by a similar procedure as for example 74 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea (95) (50 mg,0.15 mmol) to yield the title compound. Yield: (11 mg, 7%). LC/MS:Rt=1.18 min, m/z=338.2 [MH+].

Example 77: Synthesis of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea(99)

1-(4-((3-Aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea(99) was prepared by a similar procedure as for example 74 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea (95) (50 mg,0.15 mmol) using 30% 1M methanolic ammonium hydroxide in DCM to yieldthe title compound. Yield: (35 mg, 40%). LC/MS: Rt=1.16 min, m/z=366.2[MH+].

Example 78: Synthesis ofN-(3-((6-methyl-2-(3-(quinolin-2-yl)ureido)pyrimidin-4-yl)amino)propyl)acetamide(100)

A mixture of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea(99) (50 mg, 0.14 mmol), acetic anhydride (0.01 mL, 0.15 mmol), pyridine(0.07 mL, 0.87 mmol) and a catalytic amount of N,N-dimethylaminopyridinein DCM (0.5 mL) was stirred at room temperature overnight. At this timethe mixture was concentrated and purified by preparative TLC using 30%MeOH in DCM to afford the title product (100) on drying. Yield: (17 mg,31%). LC/MS: Rt=1.68 min, m/z=394.2 [MH+].

Example 79: Synthesis ofN-(2-((6-methyl-2-(3-(quinolin-2-yl)ureido)pyrimidin-4-yl)amino)ethyl)acetamide(101)

N-(2-((6-Methyl-2-(3-(quinolin-2-yl)ureido)pyrimidin-4-yl)amino)ethyl)acetamide(101) was prepared using a procedure similar to that used in example 78from1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea(98) (35 mg, 0.10 mmol). Yield: (14 mg, 35%). LC/MS: Rt=1.68 min,m/z=380.2 [MH+].

Example 80: Synthesis ofN-(2-((6-methyl-2-(3-(quinolin-2-yl)ureido)pyrimidin-4-yl)amino)ethyl)methanesulfonamide(102)

To a mixture of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea(98) (54 mg, 0.16 mmol) and triethylamine (0.04 mL, 0.32 mmol) in DCM(0.30 mL) that was cooled to 0° C. was added, methanesulfonyl chloride(0.01 mL, 0.18 mmol), and this was stirred at room temperature for 2days. At this time the mixture was concentrated and purified bypreparative TLC using 10% MeOH in DCM as eluent to give the titleproduct (102) (9 mg, 14%). LC/MS: Rt=1.77 min, m/z=416.2 [MH+].

Example 81: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-6-yl)urea(105)

Step 1: Quinoline-6-carbonyl Azide (103)

To a solution of quinoline-2-carboxylic acid (1 g, 5.6 mmol) inanhydrous DMF (10 mL) was added triethylamine (0.95 mL, 6.7 mmol)followed by diphenyl phosphoryl azide (1.46 mL, 6.7 mmol) and thismixture was stirred overnight. At this time the resulting solution wasdiluted with ethyl acetate and washed repeatedly with water. The organiclayer was washed with brine, separated and dried over sodium sulfate.After filtration the organics were concentrated and the residue purifiedby silica gel chromatography eluting with a gradient of 0-40% ethylacetate in hexanes. The title compound (103) was obtained as a whitesolid following evaporation of fractions (0.88 g, 75%). This materialwas used directly in the next step.

Step 2: 1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(quinolin-6-yl)urea (104)

A mixture of quinoline-2-carbonyl azide (103) (0.17 g, 0.83 mmol) and2-amino-4-chloro-6-methylpyrimidine (0.14 g, 0.69 mmol) in toluene (13mL) was treated with N,N-diisopropylethylamine (0.18 mL, 1.0 mmol) andthe mixture heated at 110° C. for 3 hours. The mixture was cooled andthe solvents evaporated to give a residue that was purified by flashchromatography with a gradient of 0-80% ethyl acetate in hexanes.Evaporation of the relevant fractions gave the title compound (104)(0.18 g, 76%). This material was used directly in the next step.

Step 3:1-(4-((3-(Dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-2-yl)urea(105)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(quinolin-6-yl)urea (104) (50 mg,0.15 mmol) was suspended in 2-propanol (1 mL). To this was addedtriethylamine (0.03 mL, 0.23 mmol) and thenN,N′-dimethyl-1,3-propanediamine (0.02 mL, 0.18 mmol), and the mixturewas heated at 90° C. with stirring overnight. Upon cooling the mixturewas purified by preparative TLC in 15% 3M methanolic ammonium hydroxidein DCM to give the title compound (105) (33 mg, 55%). LC/MS: Rt=0.73min, m/z=380.3 [MH+].

Example 82: Synthesis of1-(4-((2-(dimethylamino)ethyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-6-yl)urea(106)

1-(4-((2-(Dimethylamino)ethyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-6-yl)urea(106) was prepared by a similar procedure to example 81 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(quinolin-6-yl)urea (104) (50 mg,0.15 mmol) using 5% 3M methanolic ammonium hydroxide in DCM aspreparative TLC solvent. Yield: (35 mg, 67%). LC/MS: Rt=0.70 min,m/z=366.2 [MH+].

Example 83: Synthesis of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-6-yl)urea(107)

1-(4-((2-Aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-6-yl)urea(107) was prepared by a similar procedure to example 81 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(quinolin-6-yl)urea (104) (150 mg,0.45 mmol) using 30% 3M methanolic ammonium hydroxide in DCM aspreparative TLC solvent. Yield: (106 mg, 66%). LC/MS: Rt=0.67 min,m/z=328.2 [MH+].

Example 84: Synthesis of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-6-yl)urea(108)

1-(4-((3-Aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-6-yl)urea(108) was prepared by a similar procedure to example 81 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(quinolin-6-yl)urea (104) (150 mg,0.45 mmol) using 50% 3M methanolic ammonium hydroxide in DCM aspreparative TLC solvent. Yield: (135 mg, 80%). LC/MS: Rt=0.68 min,m/z=352.2 [MH+].

Example 85: Synthesis ofN-(3-((6-methyl-2-(3-(quinolin-6-yl)ureido)pyrimidin-4-yl)amino)propyl)acetamide(109)

A mixture of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-6-yl)urea(108) (50 mg, 0.14 mmol), acetic anhydride (0.01 mL, 0.15 mmol),pyridine (0.07 mL, 0.84 mmol) and a catalytic amount ofN,N-dimethylaminopyridine in DCM (1 mL) was stirred at room temperatureovernight. At this time the mixture was concentrated and purified bypreparative TLC using 5-30% 3M methanolic ammonia in DCM to afford thetitle product (109) on drying. Yield: (21 mg, 38%). LC/MS: Rt=0.99 min,m/z=394.2 [MH+].

Example 86: Synthesis ofN-(2-((6-methyl-2-(3-(quinolin-6-yl)ureido)pyrimidin-4-yl)amino)ethyl)acetamide110)

N-(2-((6-methyl-2-(3-(quinolin-6-yl)ureido)pyrimidin-4-yl)amino)ethyl)acetamide(110) was prepared using a procedure similar to that used in example 85from1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-6-yl)urea(107) (35 mg, 0.10 mmol). Yield: (15 mg, 33%). LC/MS: Rt=0.94 min,m/z=380.2 [MH+].

Example 87: Synthesis ofN-(2-((6-methyl-2-(3-(quinolin-6-yl)ureido)pyrimidin-4-yl)amino)ethyl)methanesulfonamide(111)

To a mixture of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(quinolin-6-yl)urea(107) (40 mg, 0.11 mmol) and triethylamine (0.05 mL, 0.73 mmol) in DCM(1 mL) that was cooled to 0° C. was added, methanesulfonyl chloride(0.01 mL, 0.17 mmol), and this was stirred at room temperatureovernight. The mixture was concentrated and purified by preparative TLCusing 10% 3M methanolic ammonia in DCM as eluent to give the titleproduct (111) (17 mg, 35%). LC/MS: Rt=1.0 min, m/z=416.2 [MH+].

Example 88: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-7-yl)urea(114)

Step 1: Isoquinoline-7-carbonyl Azide (112)

To a solution of isoquinoline-7-carboxylic acid (1 g, 5.6 mmol) inanhydrous DMF (10 mL) was added triethylamine (0.94 mL, 6.7 mmol)followed by diphenyl phosphoryl azide (1.49 mL, 6.7 mmol) and thismixture was stirred for 4 hours. At this time the mixture was storedovernight at −20° C. This solution was diluted with ethyl acetate andwashed repeatedly with water. The organic layer was washed with brine,separated and dried over sodium sulfate. After filtration the organicswere concentrated and the residue purified by silica gel chromatographyeluting with a gradient of 30-50% ethyl acetate in hexanes. The titlecompound (112) was obtained as a white solid following evaporation offractions (0.85 g, 77%). This material was used directly in the nextstep.

Step 2: 1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-7-yl)urea(113)

A mixture of isoquinoline-7-carbonyl azide (112) (0.85 g, 4.2 mmol) and2-amino-4-chloro-6-methylpyrimidine (0.51 g, 3.6 mmol) in toluene (30mL) was treated with N,N-diisopropylethylamine (0.93 mL, 5.4 mmol) andthe mixture heated at 100° C. for 3 hours and then at 75° C. overnight.The mixture was cooled and the mixture diluted with MeOH (10 mL).Filtration of the resulting solids afforded the title product (113)(0.69 g, 62%). This material was used directly in the next step.

Step 3:1-(4-((3-(Dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-7-yl)urea(114)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-7-yl)urea (113) (75mg, 0.24 mmol) was suspended in 2-propanol (1 mL). To this was addedtriethylamine (0.05 mL, 0.36 mmol) and thenN,N′-dimethyl-1,3-propanediamine (0.04 mL, 0.29 mmol), and the mixturewas heated at 80° C. with stirring overnight. At this time furtherportions of 2-propanol (0.5 mL), triethylamine (0.05 mL, 0.36 mmol) andN,N′-dimethyl-1,3-propanediamine (0.03 mL, 0.22 mmol) were added andheating continued for 1 day. Upon cooling the mixture was diluted withMeOH (5 mL), the resulting solids filtered and these purified bypreparative TLC in 10% 1M methanolic ammonium hydroxide in DCM to givethe title compound (114) (20 mg, 22%). LC/MS: Rt=1.00 min, m/z=380.3[MH+].

Example 89: Synthesis of1-(4-((2-(dimethylamino)ethyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-7-yl)urea(115)

1-(4-((2-(Dimethylamino)ethyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-7-yl)ureawas prepared by a similar procedure to example 88 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-7-yl)urea (113) (75mg, 0.24 mmol) except the reaction mixture was diluted with MeOH (5 mL)and the solids filtered to afford the title product (115) (31 mg, 35%).LC/MS: Rt=1.04 min, m/z=366.2 [MH+].

Example 90: Synthesis of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-7-yl)urea(116)

1-(4-((2-Aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-7-yl)urea(116) was prepared by a similar procedure to example 88 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-7-yl)urea (113) (150mg, 0.48 mmol) except the reaction mixture was diluted with MeOH (10 mL)and filtration of the resulting solids. These were purified by flashchromatography using 0-30% 3M methanolic ammonium hydroxide in DCM.Yield: (40 mg, 25%). LC/MS: Rt=0.99 min, m/z=338.2 [MH+].

Example 91: Synthesis of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-7-yl)urea(1171

1-(4-((3-Aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-7-yl)urea(117) was prepared by a similar procedure to example 90 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(isoquinolin-7-yl)urea (113) (150mg, 0.48 mmol). Yield: (43 mg, 25%). LC/MS: Rt=1.02 min, m/z=352.2[MH+].

Example 92: Synthesis ofN-(3-((2-(3-(isoquinolin-7-yl)ureido)-6-methylpyrimidin-4-yl)amino)propyl)acetamide(118)

A mixture of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-7-yl)urea(117) (50 mg, 0.14 mmol), acetic anhydride (0.01 mL, 0.15 mmol),pyridine (0.07 mL, 0.84 mmol) and a catalytic amount ofN,N-dimethylaminopyridine in DCM (1 mL) was stirred at room temperatureovernight. At this time a second portion of acetic anhydride (0.02 mL,0.21 mmol) was added and the mixture stirred for a further day. Themixture was then concentrated and purified by preparative TLC using 10%MeOH in DCM to afford the title product (118) on drying. Yield: (15 mg,27%). LC/MS: Rt=1.21 min, m/z=394.2 [MH+].

Example 93: Synthesis ofN-(2-((2-(3-(isoquinolin-7-yl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)acetamide(119)

N-(2-((2-(3-(Isoquinolin-7-yl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)acetamide(119) was prepared using a procedure similar to that used in example 92from1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-7-yl)urea(116) (57 mg, 0.16 mmol). Yield (11 mg, 17%). LC/MS: Rt=1.16 min,m/z=380.2 [MH+].

Example 94: Synthesis ofN-(2-((2-(3-(isoquinolin-7-yl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)methanesulfonamide(120)

To a mixture of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(isoquinolin-7-yl)urea(116) (29 mg, 0.09 mmol) and triethylamine (0.05 mL, 0.34 mmol) in DCM(0.3 mL) at 0° C. was added methanesulfonyl chloride (0.01 mL, 0.19mmol). The reaction mixture was stirred at room temperature overnight. Asecond portion of methanesulfonyl chloride (0.04 mL, 0.54 mmol) wasadded and stirring continued for 1 hour. The mixture was heated to 40°C. for 2 hours and then concentrated. This mixture was purified by flashchromatography using 0-10% MeOH in DCM as eluent to give the titleproduct (120) (2 mg, 6%). LC/MS: Rt=1.24 min, m/z=416.2 [MH+].

Example 95: Synthesis ofN-(2-((2-(3-(3,4-dichlorophenyl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)methanesulfonamide(123)

Step 1: Synthesis of1-(4-chloro-6-methylpyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea (121)

A 1 L round bottom flask equipped with a nitrogen inlet, condenser andmagnetic stir bar was charged with 3,4-dichlorophenylisocyanate (70.6 g,367.8 mmol) and anhydrous toluene (334 mL). The resulting solution wasstirred at room temperature. 4-chloro-6-methylpyrimidin-2-amine (50 g,334.3 mmol) was added to the solution at room temperature and theapparatus was flushed with nitrogen gas and maintained under a nitrogenatmosphere. The reaction mixture was heated to reflux for 15 hours,during which time the partially heterogeneous reaction formed a thickslurry. The resulting slurry was filtered and the solids were washedwith copious amounts of MeOH, followed by diethyl ether. The solids werecollected and dried under reduced pressure to yield the title product(121) (112 g, 99%).

Step 2:1-(4-((2-Aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(122)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea (121)(200 mg, 0.60 mmol) was suspended in 2-propanol (0.9 mL) to which wasadded triethylamine (0.13 mL, 0.9 mmol) and ethylenediamine (0.04 mL,0.60 mmol). The mixture was heated to reflux and monitored by LC/MS forreaction completion. At this time the mixture was filtered and thesolids washed with MeOH and ether to afford the title product (122) (159mg, 71%). LC/MS: Rt=1.8 min, m/z=355.1-357.1 [MH+].

Step 3:N-(2-((2-(3-(3,4-Dichlorophenyl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)methanesulfonamide(123)

To a mixture of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(122) (75 mg, 0.21 mmol) and triethylamine (0.04 mL, 0.32 mmol) in DCM(0.7 mL) at 0° C. was added methanesulfonyl chloride (0.02 mL, 0.23mmol). The reaction mixture was stirred at room temperature for 2 hoursbefore storing the mixture at −20° C. At this time, the mixture wasconcentrated and purified by column chromatography using 0-30% 3Mmethanolic ammonia in DCM as eluent to give the title product (123) (60mg, 66%). LC/MS: Rt=2.3 min, m/z=433.1-435.1 [MH+].

Example 96: Synthesis of1-([1,1′-biphenyl]-4-yl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(125)

Step 1: Synthesis of1-([1,1′-biphenyl]-4-yl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea (124)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (0.5 g, 3.4 mmol) and4-biphenyl isocyanate (0.82 g, 4.1 mmol) and toluene (3.1 mL) wasstirred at room temperature and then heated at 110° C. overnight. Theresulting slurry was filtered and the solids washed with diethyl etherto yield the title product (124) (1.1 g, 98%). This material was useddirectly in the next step.

Step 2:1-([1,1′-Biphenyl]-4-yl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(125)

1-([1,1′-Biphenyl]-4-yl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea (124)(200 mg, 0.57 mmol) was suspended in 2-propanol (0.5 mL) to which wasadded triethylamine (0.12 mL, 0.86 mmol) and3-(dimethylamino)-1-propylamine (0.09 mL, 0.69 mmol). The mixture washeated to 80° C. for 2 hours when a precipitate formed. On cooling, themixture was filtered to afford the title product (125) (171 mg, 70%).LC/MS: Rt=1.70 min, m/z=405.3 [MH+].

Example 97: Synthesis of1-([1,1′-biphenyl]-4-yl)-3-(4-(ethylamino)-6-methylpyrimidin-2-yl)urea(126)

1-([1,1′-Biphenyl]-4-yl)-3-(4-(ethylamino)-6-methylpyrimidin-2-yl)urea(126) was prepared by a procedure similar to that for example 96 from1-([1,1′-biphenyl]-4-yl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea (124)(200 mg, 0.57 mmol) and ethylamine. Yield: (146 mg, 70%). LC/MS: Rt=2.84min, m/z=348.2 [MH+].

Example 98: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(3-phenoxyphenyl)urea(128)

Step 1: Synthesis of1-(4-chloro-6-methylpyrimidin-2-yl)-3-(3-phenoxyphenyl)urea (127)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (0.5 g, 3.4 mmol) and3-phenoxyphenyl isocyanate (0.87 g, 4.1 mmol) and toluene (3.1 mL) wasstirred at room temperature and then heated at 110° C. overnight. Theresulting slurry was filtered and the solids washed with diethyl etherto yield the title product (127) (1.1 g, 89%). This material was useddirectly in the next step.

Step 2:1-(4-((3-(Dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(3-phenoxyphenyl)urea(128)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(3-phenoxyphenyl)urea (127) (200mg, 0.55 mmol) was suspended in 2-propanol (0.5 mL) to which was addedtriethylamine (0.11 mL, 0.83 mmol) and 3-(dimethylamino)-1-propylamine(0.09 mL, 0.69 mmol). The mixture was heated to 80° C. for 2 hours whena precipitate formed. On cooling the mixture was filtered to afford thetitle product (128) (200 mg, 83%). LC/MS: Rt=1.73 min, m/z=421.3 [MH+].

Example 99: Synthesis of1-([1,1′-biphenyl]-3-yl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(131)

Step 1: Synthesis of [1,1′-biphenyl]-3-carbonyl azide (129)

To a solution of [1,1′-biphenyl]-3-carboxylic acid (1 g, 4.9 mmol) inanhydrous DMF (10 mL) was added triethylamine (0.77 mL, 5.4 mmol)followed by diphenyl phosphoryl azide (1.28 mL, 5.4 mmol) and thismixture was stirred until the reaction was complete as judged by LC/MS.This solution was diluted with ethyl acetate and washed repeatedly withwater. The organic layer was washed with brine, separated and dried oversodium sulfate. After filtration the organics were concentrated and theresidue used directly in the next step.

Step 2: Synthesis of1-([1,1′-biphenyl]-3-yl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea (129)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (0.5 g, 3.4 mmol) and[1,1′-biphenyl]-3-carbonyl azide (129) (0.98 g, 4.1 mmol) in toluene (65mL) was treated with N,N-diisopropylethylamine (0.47 mL, 5.2 mmol) andthe mixture heated at 100° C. for 3 hours. The mixture was cooled andthe mixture diluted with MeOH (10 mL). Filtration of the resultingsolids afforded the title product (130) (0.28 g, 24%). This material wasused directly in the next step.

Step 3: Synthesis of1-([1,1′-biphenyl]-3-yl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(131)

1-([1,1′-biphenyl]-3-yl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea (130)(200 mg, 0.57 mmol) was suspended in 2-propanol (0.5 mL) to which wasadded triethylamine (0.12 mL, 0.86 mmol) and3-(dimethylamino)-1-propylamine (0.09 mL, 0.69 mmol). The mixture washeated to 80° C. for 2 hours when a precipitate formed. On cooling, themixture was filtered and the solids purified by column chromatography ina gradient of 0-40% 3M methanolic ammonia in DCM to afford the titleproduct (131) (100 mg, 41%). LC/MS: Rt=1.99 min, m/z=405.3 [MH+].

Example 100: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(4-phenoxyphenyl)urea(133)

Step 1: Synthesis of1-(4-chloro-6-methylpyrimidin-2-yl)-3-(4-phenoxyphenyl)urea (132)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (0.5 g, 3.4 mmol) and4-phenoxyphenyl isocyanate (0.87 g, 4.1 mmol) and toluene (3.1 mL) wasstirred at room temperature and then heated at 110° C. overnight. Theresulting slurry was filtered and the solids washed with diethyl etherto yield the title product (132) (1.1 g, 89%). This material was useddirectly in the next step.

Step 2:1-(4-((3-(Dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(4-phenoxyphenyl)urea(133)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(4-phenoxyphenyl)urea (132) (200mg, 0.55 mmol) was suspended in 2-propanol (0.5 mL) to which was addedtriethylamine (0.11 mL, 0.82 mmol) and 3-(dimethylamino)-1-propylamine(0.09 mL, 0.66 mmol). The mixture was heated to 80° C. for 2 hours whena precipitate formed. On cooling, the mixture was filtered to afford thetitle product (133) (150 mg, 62%). LC/MS: Rt=1.78 min, m/z=421.0 [MH+].

Example 101: Synthesis of1-(4-(ethylamino)-6-methylpyrimidin-2-yl)-3-(4-phenoxyphenyl)urea (134)

1-(4-(Ethylamino)-6-methylpyrimidin-2-yl)-3-(4-phenoxyphenyl)urea (134)was prepared by a procedure similar to that for example 100 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(4-phenoxyphenyl)urea (132) (200mg, 0.57 mmol) and ethylamine, where the reaction product was purifiedby column chromatography using 3M methanolic ammonia in DCM. Yield: (82mg, 39%). LC/MS: Rt=2.43 min, m/z=363.9 [MH+].

Example 102: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(4-isopropoxyphenyl)urea(136)

Step 1: Synthesis of1-(4-chloro-6-methylpyrimidin-2-yl)-3-(4-isopropoxyphenyl)urea (135)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (1.3 g, 8.8 mmol) and4-methylethoxybenzene isocyanate (1.72 g, 9.7 mmol) and toluene (8.8 mL)was stirred at room temperature and then heated at 110° C. for 4 hours.MeOH (10 mL) was added and the resulting mixture concentrated to a solidresidue that was crystallized from MeOH to yield the title product (135)(0.73 g, 26%). This material was used directly in the next step.

Step 2:1-(4-((3-(Dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(4-isopropoxyphenyl)urea(136)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(4-isopropoxyphenyl)urea (135) (75mg, 0.23 mmol) was suspended in 2-propanol (0.47 mL) to which was addedtriethylamine (0.05 mL, 0.35 mmol) and 3-(dimethylamino)-1-propylamine(0.04 mL, 0.26 mmol). The mixture was heated to 80° C. for overnightwhen a precipitate formed. On cooling, the mixture was filtered and thesolids chromatographed using 0-20% 1M methanolic ammonia in DCM toafford the title product (136) (24 mg, 26%). LC/MS: Rt=1.58 min,m/z=387.3 [MH+].

Example 103: Synthesis of1-(4-((2-(dimethylamino)ethyl)amino)-6-methylpyrimidin-2-yl)-3-(4-isopropoxyphenyl)urea(137)

1-(4-((2-(Dimethylamino)ethyl)amino)-6-methylpyrimidin-2-yl)-3-(4-isopropoxyphenyl)urea(137) was prepared by a procedure similar to that for example 102 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(4-isopropoxyphenyl)urea (135) (75mg, 0.23 mmol) and 2-dimethylaminoethylamine. Yield: (23 mg, 27%).LC/MS: Rt=1.52 min, m/z=373.3 [MH+].

Example 104: Synthesis ofN-(2-((2-(3-(4-isopropoxyphenyl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)methanesulfonamide(139)

Step 1:1-(4-((2-Aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(4-isopropoxyphenyl)urea(138)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(4-isopropoxyphenyl)urea (135)(150 mg, 0.47 mmol) was suspended in 2-propanol (0.9 mL) to which wasadded triethylamine (0.10 mL, 0.7 mmol) and ethylenediamine (0.04 mL,0.56 mmol). The mixture was heated to reflux and heated overnight. Atthis time the mixture was filtered and the solids chromatographed using10-30% 1M methanolic ammonia in DCM. Purified fractions were evaporatedand partitioned between DCM and saturated sodium bicarbonate solutionand the aqueous layer back extracted with DCM. The combined organicfractions were dried over anhydrous sodium sulfate, filtered andevaporated to afford the title product (138) (40 mg, 26%). This materialwas used directly in the next step.

Step 2:N-(2-((2-(3-(4-Isopropoxyphenyl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)methanesulfonamide(139)

To a mixture of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(4-isopropoxyphenyl)urea(138) (64 mg, 0.18 mmol) and pyridine (0.74 mL, 0.18 mmol) at 0° C. wasadded methanesulfonyl chloride (0.04 mL, 0.55 mmol). The reactionmixture was stirred at room temperature for 4 hours. At this timeadditional methanesulfonyl chloride (0.05 mL, 0.69 mmol) was added andstirring continued overnight. The mixture was quenched with MeOH (2 mL),concentrated and the residue purified by column chromatography using0-10% MeOH in DCM as eluent to give the title product (139) (23 mg,30%). LC/MS: Rt=1.99 min, m/z=424.2 [MH+].

Example 105: Synthesis ofN-(2-((2-(3-(4-isopropoxyphenyl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)acetamide(140)

A mixture of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(4-isopropoxyphenyl)urea(138) (35 mg, 0.10 mmol), acetic anhydride (0.01 mL, 0.11 mmol),pyridine (0.05 mL, 0.62 mmol) and a catalytic amount ofN,N-dimethylaminopyridine in DCM (0.5 mL) was stirred at roomtemperature overnight. The mixture was then concentrated andchromatographed using 10% MeOH in DCM to afford the title product (140)on drying. Yield: (13 mg, 32%). LC/MS: Rt=1.84 min, m/z=387.3 [MH+].

Example 106: Synthesis ofN-(3-((2-(3-(4-isopropoxyphenyl)ureido)-6-methylpyrimidin-4-yl)amino)propyl)acetamide(142)

Step 1:1-(4-((3-Aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(4-isopropoxyphenyl)urea(141)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(4-isopropoxyphenyl)urea (135)(150 mg, 0.47 mmol) was suspended in 2-propanol (0.5 mL) to which wasadded triethylamine (0.10 mL, 0.7 mmol) and propane-1,3-diamine (0.05mL, 0.56 mmol). The mixture was heated to reflux and heated overnight.At this time the mixture was filtered and the solids chromatographedusing 10-30% 1M methanolic ammonia in DCM Purified fractions wereevaporated and partitioned between DCM and saturated sodium bicarbonatesolution and the aqueous layer back extracted with DCM. The combinedorganic fractions were dried over anhydrous sodium sulfate, filtered andevaporated to afford the title product (141) (22 mg, 13%). This materialwas used directly in the next step.

Step 2:N-(3-((2-(3-(4-Isopropoxyphenyl)ureido)-6-methylpyrimidin-4-yl)amino)propyl)acetamide(142)

A mixture of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(4-isopropoxyphenyl)urea(141) (22 mg, 0.06 mmol), acetic anhydride (0.006 mL, 0.07 mmol),piperidine (0.07 mL, 0.30 mmol) and a catalytic amount ofN,N-dimethylaminopyridine in DCM (0.5 mL) was stirred at roomtemperature. A second portion of acetic anhydride (0.08 mL, 0.93 mmol)was added and the mixture stirred overnight. DCM (1 mL) was added andthe mixture was then chromatographed using 0-10% MeOH in DCM to affordthe title product (142) on drying. Yield: (15 mg, 57%). LC/MS: Rt=1.83min, m/z=401.3 [MH+].

Example 107: Synthesis of1-(4-methyl-6-(methylamino)pyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(144)

Step 1:1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(143)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (4.2 g, 29.3 mmol) and4-(trifluoromethoxy)phenyl isocyanate (6.5 g, 32.2 mmol) in dioxane (39mL) was heated for 7 hours at 100° C. MeOH (40 mL) was added and themixture stirred overnight. The solids were filtered to yield a firstcrop of the title product (143). Concentration of the filtrate yielded asolid which was crystallized from MeOH (40 mL) to yield a second portion(7.4 g, 73%).

Step 2:1-(4-Methyl-6-(methylamino)pyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(144)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(p-trifluoromethoxyphenyl)urea(143) (75 mg, 0.22 mmol), triethylamine (0.04 mL, 0.32 mmol) andmethylamine (2M in THF: 0.13 mL, 0.26 mmol) in 2-propanol (0.43 mL) washeated for overnight at 80° C. The reaction mixture was cooled andtreated with MeOH (3 mL). A white precipitate was filtered, washed withMeOH and air dried to yield the title compound (144) (44 mg, 59%).LC/MS: Rt=2.17 min, m/z=342.2 [MH+].

Example 108: Synthesis of1-(4-((2-hydroxyethyl)amino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(145)

1-(4-((2-Hydroxyethyl)amino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(145) was prepared by a procedure similar to that for example 107 from1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(p-trifluoromethoxyphenyl)urea(143) (75 mg, 0.22 mmol) and ethanolamine. Yield: (52 mg, 60%). LC/MS:Rt=2.17 min, m/z=372.2 [MH+].

Example 109: Synthesis of1-(4-(methoxyamino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(146)

1-(4-(Methoxyamino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(146) was prepared by a procedure similar to that for example 107 from1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(p-trifluoromethoxyphenyl)urea(143) (100 mg, 0.29 mmol) and O-Methylhydroxylamine hydrochloride. Theproduct was chromatographed in stepwise fashion using 5% and then 20%MeOH in DCM. Yield: (12 mg, 11%). LC/MS: Rt=3.32 min, m/z=358.2 [MH+].

Example 110: Synthesis of1-(4-(hydroxyamino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(147)

1-(4-(Hydroxyamino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(147) was prepared by a procedure similar to that for example 107 from1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(p-trifluoromethoxyphenyl)urea(143) (75 mg, 0.22 mmol) and hydroxylamine hydrochloride. The productwas chromatographed in a gradient of 0-20% 1M methanolic ammonia in DCM.Yield: (11 mg, 15%). LC/MS: Rt=2.12 min, m/z=358.2 [MH+].

Example 111: Synthesis of1-(3-chloro-4-(trifluoromethoxy)phenyl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(149)

Step 1:1-(3-Chloro-4-(trifluoromethoxy)phenyl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea(148)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (0.60 g, 4.2 mmol) and3-chloro-4-(trifluoromethoxy)phenyl isocyanate (1.1 g, 4.6 mmol) intoluene (8 mL) was heated overnight at 100° C. MeOH (10 mL) was addedand the mixture was filtered to yield a solid which was washed with MeOH(5 mL) to afford the title product (148) (321 mg, 20%).

Step 2:1-(3-Chloro-4-(trifluoromethoxy)phenyl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(149)

A mixture of1-(3-chloro-4-(trifluoromethoxy)phenyl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea(148) (75 mg, 0.20 mmol), triethylamine (0.04 mL, 0.30 mmol) and3-(dimethylamino)-1-propylamine (0.03 mL, 0.24 mmol) in 2-propanol (0.40mL) was heated overnight at 80° C. The reaction mixture was cooled andtreated with MeOH (3 mL). A white precipitate was filtered, washed withMeOH and air dried to yield the title compound (149) (44 mg, 50%).LC/MS: Rt=2.10 min, m/z=447.2-449.2 [MH⁺].

Example 112: Synthesis of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(3-chloro-4-(trifluoromethoxy)phenyl)urea(150)

1-(4-((2-Aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(3-chloro-4-(trifluoromethoxy)phenyl)urea(150) was prepared by a procedure similar to that for example 111 from1-(3-chloro-4-(trifluoromethoxy)phenyl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea(148) (100 mg, 0.26 mmol) and ethylenediamine. Yield: (63 mg, 60%).LC/MS: Rt=1.93 min, m/z=403.1-405.1 [MH+].

Example 113 Synthesis ofN-(2-((2-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)methanesulfonamide(151)

To a mixture of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(4-isopropoxyphenyl)urea(150) (117 mg, 0.29 mmol) and pyridine (1.16 mL, 0.29 mmol) at 0° C. wasadded methanesulfonyl chloride (0.04 mL, 0.55 mmol). The reactionmixture was stirred at room temperature for 5 hours. The mixture wasconcentrated and dissolved in DCM, and then extracted with saturatedsodium bicarbonate solution. Washing of the aqueous layer with twovolumes of DCM gave a combined organic fraction that was dried oversodium sulfate and evaporated to give the title product (151) (51 mg,36%). LC/MS: Rt=2.40 min, m/z=483.1-485.1 [MH+].

Example 114: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(3-methyl-4-(trifluoromethoxy)phenyl)urea(153)

Step 1:1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(3-methyl-4-(trifluoromethoxy)phenyl)urea(152)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (0.65 g, 4.5 mmol) and3-methyl-4-(trifluoromethoxy)phenyl isocyanate (1.1 g, 5.0 mmol) intoluene (9 mL) was heated overnight at 80° C. MeOH (5 mL) was added andthe mixture was filtered to yield a solid which was washed with MeOH (5mL) to afford the title product (152) (350 mg, 21%).

Step 2:1-(4-((3-(Dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(3-methyl-4-(trifluoromethoxy)phenyl)urea(153)

A mixture of1-(4-chloro-6-methylpyrimidin-2-yl)-3-(3-methyl-4-(trifluoromethoxy)phenyl)urea(152) (75 mg, 0.21 mmol), triethylamine (0.04 mL, 0.31 mmol) and3-(dimethylamino)-1-propylamine (0.03 mL, 0.25 mmol) in 2-propanol (0.40mL) was heated for overnight at 80° C. The reaction mixture was cooledand treated with MeOH (3 mL). A white precipitate was filtered and thenchromatographed using 0-30% 1M methanolic ammonia in DCM to yield thetitle compound (153) (43 mg, 48%). LC/MS: Rt=1.80 min, m/z=427.2 [MH⁺].

Example 115: Synthesis of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(4-benzoylphenyl)urea(155)

Step 1: 1-(4-Benzoylphenyl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea(154)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (1.0 g, 6.8 mmol) and4-benzoylphenyl isocyanate (1.9 g, 8.1 mmol) in toluene (6.4 mL) washeated overnight at 110° C. The mixture was filtered to yield a solidwhich was washed with ether to afford the title product (154) (2.5 mg,96%).

Step 2:1-(4-((3-Aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(4-benzoylphenyl)urea(155)

A mixture of 1-(4-benzoylphenyl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea(154) (103 mg, 1.36 mmol), triethylamine (0.38 mL, 2.7 mmol) and1,3-diaminopropane (0.12 mL, 1.36 mmol) in 2-propanol (0.40 mL) washeated overnight at 80° C. A white precipitate was filtered to yield thetitle compound (155) (165 mg, 57%). LC/MS: Rt=1.84 min, m/z=405.3 [MH⁺].

Example 116: Synthesis of1-(3,4-dichlorophenyl)-3-(4-((3-(dimethylamino)propyl)amino)pyrimidin-2-yl)urea(157)

Step 1: 1-(4-Chloropyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea (156)

A mixture of 2-amino-4-chloro-pyrimidine (2.5 g, 18.5 mmol) and3,4-dichlorophenyl isocyanate (3.9 g, 20.4 mmol) in toluene (20 mL) washeated overnight at reflux. The mixture was filtered to yield a solidwhich was washed with ethanol and then ether to afford the title product(156) (4.5 g, 74%).

Step 2:1-(3,4-Dichlorophenyl)-3-(4-((3-(dimethylamino)propyl)amino)pyrimidin-2-yl)urea(157)

A mixture of 1-(4-chloropyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea (156)(250 mg, 0.78 mmol), triethylamine (0.13 mL, 0.9 mmol) andN,N′-dimethyl-1,3-propanediamine (0.22 mL, 1.9 mmol) in 2-propanol (3mL) was heated overnight at 80° C. A white precipitate was filtered andwashed with absolute ethanol to yield the title compound (157) (152 mg,48%). LC/MS: Rt=1.78 min, m/z=383.2-385.2 [MH+].

Example 117: Synthesis of1-(3,4-dichlorophenyl)-3-(4-(hydroxyamino)pyrimidin-2-yl)urea (158)

1-(3,4-Dichlorophenyl)-3-(4-(hydroxyamino)pyrimidin-2-yl)urea (158) wasprepared by a procedure similar to that for example 116 from1-(4-chloropyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea (156) (200 mg,0.63 mmol) and hydroxylamine hydrochloride. Yield: (63 mg, 60%). LC/MS:Rt=2.29 min, m/z=314.1-316.1 [MH+].

Example 118: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)pyrimidin-2-yl)-3-(naphthalen-2-yl)urea(160)

Step 1: 1-(4-Chloropyrimidin-2-yl)-3-(naphthalen-2-yl)urea (159)

A mixture of 2-isocyanatonaphthalene (1) (0.94 g, 5.6 mmol) and2-amino-4-chloro-pyrimidine (0.67 g, 5.0 mmol) and toluene (25 mL) washeated at reflux overnight. On cooling, the precipitates formed werefiltered and washed with ethanol and then ether to afford the titlecompound (159) (0.9 g, 58%). LC/MS: Rt=3.96 min, m/z=299.1 [MH⁺].

Step 2:1-(4-((3-(Dimethylamino)propyl)amino)pyrimidin-2-yl)-3-(naphthalen-2-yl)urea(160)

1-(4-Chloropyrimidin-2-yl)-3-(naphthalen-2-yl)urea (159) (200 mg, 0.67mmol) was suspended in 2-propanol (3 mL). To this was addedtriethylamine (0.11 mL, 0.80 mmol) and thenN,N′-dimethyl-1,3-propanediamine (0.19 mL, 1.6 mmol), and the mixturewas heated at 80° C. with stirring overnight. Upon cooling the mixturewas filtered and washed with ethanol to give the title compound (160)(100 mg, 39%). LC/MS: Method 1: Rt=1.61 min, m/z=365.3 [MH+].

Example 119: Synthesis of1-(4-(hydroxyamino)pyrimidin-2-yl)-3-(naphthalen-2-yl)urea (161)

1-(4-(Hydroxyamino)pyrimidin-2-yl)-3-(naphthalen-2-yl)urea (161) wasprepared by a procedure similar to that for example 118 from1-(4-chloropyrimidin-2-yl)-3-(naphthalen-2-yl)urea (159) (200 mg, 0.67mmol) and hydroxylamine hydrochloride. Yield: (177 mg, 85%). LC/MS:Rt=1.97 min, m/z=296.1 [MH+].

Example 120: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)pyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(163)

Step 1: 1-(4-Chloropyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(162)

A mixture of 2-amino-4-chloropyrimidine (2 g, 15.4 mmol) and4-(trifluoromethoxy)phenyl isocyanate (3.4 g, 17.0 mmol) in dioxane (21mL) was heated for 2.5 hours at 100° C. MeOH (30 mL) was added and themixture concentrated. The solids were stirred in MeOH (40 mL) for 2hours and then filtered to yield the title product (162) (2.7 g, 52%).LC/MS: Rt=4.00 min, m/z=334.1 [MH⁺].

Step 2:1-(4-((3-(Dimethylamino)propyl)amino)pyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(163)

A mixture of1-(4-chloropyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea (162) (75mg, 0.23 mmol), triethylamine (0.05 mL, 0.34 mmol) andN,N′-dimethyl-1,3-propanediamine (0.03 mL, 0.27 mmol) in 2-propanol(0.45 mL) was heated for 4 hours at 80° C. The reaction mixture waspurified by preparative TLC using 10% 1M methanolic ammonia in DCM toyield the title compound (163) (29 mg, 32%). LC/MS: Rt=1.74 min,m/z=399.2 [MH⁺].

Example 121: Synthesis of1-(3,4-dichlorophenyl)-3-(4-((3-(dimethylamino)propyl)amino)-5-fluoropyrimidin-2-yl)urea(168)

Step 1: (1-Ethoxy-2-fluoro-1,3-dioxopropan-2-yl)sodium (164)

To sodium hydride (60% in mineral oil: 6.8 g, 169 mmol) was addeddiethyl ether (240 mL) under a nitrogen stream with cooling (ice bath).Absolute ethanol (0.8 mL) was added followed by ethyl formate (12.9 g,169 mmol) followed by a solution of ethyl fluoroacetate (18.1 g, 169mmol) in diethyl ether (100 mL) dropwise over 1.5-2 hours. This mixturewas allowed to stir at room temperature overnight before evaporation ofsolvents to yield the title compound (164) (26.4 g, 100%) that was useddirectly in the next step.

Step 2: 2-Amino-5-fluoropyrimidin-4(5H)-one (165)

To a solution of sodium ethoxide (21% weight in ethanol: 189 mL, 507mmol) was added guanidine hydrochloride (51.0 g, 507 mmol) which wasstirred at room temperature for 30 minutes with the formation of aprecipitate. The filtrate was added to a solution of(1-ethoxy-2-fluoro-1,3-dioxopropan-2-yl)sodium (164) (26.4 g, 169 mmol)in absolute ethanol (177 mL). This mixture was heated overnight at 90°C. before cooling and concentration. Neutralization of the concentrateat 0° C. with 6N HCl solution gave a suspension that was stirred for 1hour at this temperature. Filtration provided a brown solid that waschromatographed by reverse phase using 0-7% water in acetonitrile toafford the title compound (165) (5.1 g, 22%) as a pale yellow solid thatwas used directly in the next step.

Step 3: 4-Chloro-5-fluoropyrimidin-2-amine (166)

2-Amino-5-fluoropyrimidin-4(5H)-one (165) (5.1 g, 37 mmol) was treatedwith phosphoryl chloride (24 mL, 255 mmol) and this mixture heated for 4hours. The homogeneous mixture was cooled and poured onto ice. Thistemperature was maintained while adding water (500 mL) and adjustment ofthe pH to 7. The aqueous layer was extracted with ethyl acetate (3×) andthe organics washed with brine. Drying over sodium sulfate, filtrationand evaporation of the solvent yielded a solid that was chromatographedin 0-25% ethyl acetate in hexanes. The purified material wascrystallized from DCM in hexanes to afford the title product (166) (0.99g, 17%). LC/MS: Rt=1.87 min, m/z=148.0 [MH⁺].

Step 4: 1-(4-Chloro-5-fluoropyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(167)

A mixture of 4-chloro-5-fluoropyrimidin-2-amine (166) (0.1 g, 0.64 mmol)and 3,4-dichlorophenyl isocyanate (0.24 g, 1.29 mmol) in dioxane (3 mL)was heated overnight at 90° C. The mixture was chromatographed in 0-60%ethyl acetate in hexanes to afford the title product (167) (75 mg, 35%).

Step 5:1-(3,4-Dichlorophenyl)-3-(4-((3-(dimethylamino)propyl)amino)-5-fluoropyrimidin-2-yl)urea(168)

A mixture of1-(4-chloro-5-fluoropyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea (167) (20mg, 0.06 mmol), triethylamine (0.02 mL, 0.17 mmol) andN,N′-dimethyl-1,3-propanediamine (0.01 mL, 0.11 mmol) in 2-propanol (1mL) was heated overnight at 90° C. A white precipitate was filtered andwashed with absolute ethanol/ether (1/1) to yield the title compound(168) (14 mg, 59%). LC/MS: Rt=2.38 min, m/z=401.2-403.1 [MH⁺].

Example 122: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-5-fluoropyrimidin-2-yl)-3-(naphthalen-2-yl)urea(170)

Step 1: 1-(4-Chloro-5-fluoropyrimidin-2-yl)-3-(naphthalen-2-yl)urea(169)

A mixture of 2-isocyanatonaphthalene (1) (0.22 g, 1.3 mmol) and4-chloro-5-fluoropyrimidin-2-amine (166) (0.1 g, 0.64 mmol) and dioxane(3 mL) was heated at 90° C. overnight. The mixture was chromatographedin 0-60% ethyl acetate in hexanes to afford the title product (169) andcrystallized from DCM/MeOH/hexanes (55 mg, 26%).

Step 2:1-(4-((3-(Dimethylamino)propyl)amino)-5-fluoropyrimidin-2-yl)-3-(naphthalen-2-yl)urea(170)

1-(4-Chloro-5-fluoropyrimidin-2-yl)-3-(naphthalen-2-yl)urea (169) (23mg, 0.07 mmol) was suspended in 2-propanol (1 mL). To this was addedtriethylamine (0.03 mL, 0.21 mmol) and thenN,N′-dimethyl-1,3-propanediamine (0.02 mL, 0.16 mmol), and the mixturewas heated at 90° C. with stirring overnight. Upon cooling the mixturewas chromatographed in 0-30% 1M methanolic ammonia in DCM to give thetitle compound (170) (8 mg, 29%). LC/MS: Method 1: Rt=2.20 min,m/z=383.2 [MH+].

Example 123: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-5-fluoropyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(172)

Step 1:1-(4-Chloro-5-fluoropyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(171)

A mixture of 4-(trifluoromethyoxy)phenylisocyanate (0.27 g, 1.3 mmol)and 4-chloro-5-fluoropyrimidin-2-amine (166) (0.1 g, 0.64 mmol) anddioxane (3 mL) was heated at 90° C. overnight. The mixture waschromatographed in 0-30% ethyl acetate in hexanes to afford the titleproduct (171) (84 mg, 35%).

Step 2:1-(4-((3-(dimethylamino)propyl)amino)-5-fluoropyrimidin-2-yl)-3-(naphthalen-2-yl)urea(172)

1-(4-Chloro-5-fluoropyrimidin-2-yl)-3-(naphthalen-2-yl)urea (171) (20mg, 0.05 mmol) was suspended in 2-propanol (1 mL). To this was addedtriethylamine (0.02 mL, 0.16 mmol) and thenN,N′-dimethyl-1,3-propanediamine (0.01 mL, 0.11 mmol), and the mixturewas heated at 90° C. with stirring overnight. Upon cooling the mixturewas chromatographed in 0-25% 1M methanolic ammonia in DCM to give thetitle compound (172) (6 mg, 25%). LC/MS: Method 1: Rt=2.35 min,m/z=417.2 [MH+].

Example 124: Synthesis of1-(3,4-dichlorophenyl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)ureadimethanesulfonic acid salt (174)

Step 1:1-(3,4-Dichlorophenyl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(173)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea (Example95, compound 121) (50 g, 149 mmol) was suspended in 2-propanol (299 mL)to which was added triethylamine (31.5 mL, 224 mmol) andN,N′-dimethyl-1,3-propanediamine (22.8 mL, 179 mmol). The mixture washeated to reflux overnight. After cooling, the mixture was filtered andthe solids washed with MeOH. The solid obtained was slurried in diethylether with stirring for 30 minutes before filtration and drying of thesolid to afford the title product (173) (55.3 g, 89%). This material wasused directly in the next step.

Step 2:1-(3,4-Dichlorophenyl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)ureadimethanesulfonic acid salt (174)

1-(3,4-Dichlorophenyl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(173) (10 g, 25 mmol) was suspended in DCM (101 mL) to which was addedmethansulfonic acid (3.9 mL, 60 mmol). The mixture was agitated to forma solution which on stirring became a suspension. Solvents were removedand a minimum amount of methanol added to dissolve. MTBE was added tothe point of turbidity when the mixture was stirred for 2 hours. Thismixture was filtered to afford the title product (174) (10.2 g, 69%).LC/MS: Method 1: Rt=0.35, m/z=397.2-399.2 [MH+].

Example 125: Synthesis of1-(4-amino-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)-phenyl)urea(176)

Step 1:1-(4-((4-Methoxybenzyl)amino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoro-methoxy)phenyl)urea(175)

1-(4-((4-Methoxybenzyl)amino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)-phenyl)urea(175) was prepared by a similar procedure as for Example 107 from1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(p-trifluoromethoxyphenyl)urea(143) (100 mg, 0.29 mmol) and 4-methoxybenzylamine (108 mg, 85%). Thismaterial was used directly in the next step.

Step 2:1-(4-Amino-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(176)

1-(4-((4-Methoxybenzyl)amino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)-phenyl)urea(175) (108 mg, 0.24 mmol) was dissolved in trifluoroacetic acid (4.2mL). The mixture was heated overnight at 80° C. Volatiles wereevaporated and the solid suspended in saturated aqueous sodiumbicarbonate solution. After 30 minutes, the solid was filtered to affordthe title product (176) (51 mg, 64%). LC/MS: Rt=2.40 min, m/z=328.1[MH+].

Example 126: Synthesis of1-(3,4-dichlorophenyl)-3-(4-isopropyl-6-((3-(methyl-amino)propyl)amino)pyrimidin-2-yl)urea(184)

Step 1: 2-Amino-6-isopropylpyrimidin-4(5H)-one (180)

To a suspension of ethyl isobutyrylacetate (5 g, 30 mmol) and guanidinehydrochloride (4.5 g, 45 mmol) in absolute ethanol 60 mL was addedsodium methoxide (25% in methanol: 2.5 g, 45 mmol). The resultingmixture was sealed in a pressure seal vessel and heated to 100° C.overnight. The solvent was removed in vacuo and the resulting residuewas purified by flash chromatography (gradient, 20-80% EtOAc in hexanes;0-20% MeOH in dichloromethane) to obtain the desired compound as a paleyellow solid (3.7 g, 76%). This material was used directly in the nextstep.

Step 2: 4-Chloro-6-isopropylpyrimidin-2-amine (181)

2-Amino-6-isopropylpyrimidin-4(5H)-one (180) (3.7 g, 24.0 mmol) wastreated with phosphoryl chloride (16 mL) and this mixture heated for 4hours. The homogeneous mixture was cooled and poured onto ice. Thistemperature was maintained while adding water (500 mL) and adjustment ofthe pH to 7. The aqueous layer was extracted with ethyl acetate (3×) andthe organics washed with brine. Drying over sodium sulfate, filtrationand evaporation of the solvent yielded a solid that was chromatographedin 0-25% ethyl acetate in hexanes. The purified material wascrystallized from dichloromethane in hexanes to afford the title product(181) (2.1 g, 51%). This material was used directly in the next step.

Step 3: 1-(4-Chloro-6-isopropylpyrimidin-2-yl)-3-(3,4-dichlorophen1)urea (182)

A mixture of 4-chloro-6-isopropylpyrimidin-2-amine (0.70 g, 3.78 mmol)and 3,4-dichlorophenyl-isocyanate (0.77 g, 3.78 mmol) in toluene (5 mL)was heated to 100° C. for 3 h. The precipitate formed was collectedthrough filtration, and washed with ether/hexanes (1:1) to give thetitle compound (182) as a white solid (1.38, 94%). LC/MS: Rt=5.06 min,m/z=359.1, 361.1 [MH+]. This material was used directly in the nextstep.

Step 3: tert-Butyl(3-((2-(3-(3,4-dichlorophenyl)ureido)-6-isopropylpyrimidin-4-yl)amino)propyl)(methyl)carbamate(183)

To a suspension of1-(4-chloro-6-isopropylpyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea (182)(0.10 g, 0.26 mmol) in 2-propanol (5 mL) was added3-(N-Boc-N-methylamino)-propylamine (0.08 g, 0.39 mmol) andtriethylamine (0.11 mL, 0.79 mmol). The mixture was heated to 95° C.overnight. The reaction was concentrated and used directly for thefollowing deprotection. (0.14 g, 100%)

Step 4:1-(3,4-Dichlorophenyl)-3-(4-isopropyl-6-((3-(methylamino)propyl)-amino)pyrimidin-2-yl)urea(184)

To a solution of crude tert-butyl(3-((2-(3-(3,4-dichlorophenyl)ureido)-6-isopropylpyrimidin-4-yl)amino)propyl)(methyl)carbamate(183) (0.14 g) in dichloromethane (1.25 mL) was added TFA (1.25 mL). Themixture was stirred at room temperature. After 3 h stirring, thereaction mixture was concentrated and neutralized with cold 5% aqueousammonia, concentrated and purified by flash chromatography (gradient,0-30% 1M NH₃/MeOH in dichloromethane) to obtain the title compound (184)as a white solid. (0.04 g, 37%). LC/MS: Rt=1.89 min, m/z=411.2, 413.2[MH+].

Example 127: Synthesis of1-(3,4-dichlorophenyl)-3-(4-(hydroxyamino)-6-isopropyl-pyrimidin-2-yl)urea(185)

Step 1:1-(3,4-dichlorophenyl)-3-(4-(hydroxyamino)-6-isopropylpyrimidin-2-yl)urea(185)

To a mixture of1-(4-chloro-6-isopropylpyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea (182)(0.10 g, 0.26 mmol) and hydroxylamine hydrochloride (0.19 g, 2.6 mmol)in 2-propanol (5 mL) was added triethylamine (0.41 mL, 2.9 mmol), andthe resulting mixture was heated to 95° C. for 3 h. The mixture wasconcentrated and purified by flash chromatography (gradient, 0-15% 1MNH₃/MeOH in dichloromethane) to obtain the title compound (185) as awhite solid. (0.06 g, 62%). LC/MS: Rt=2.69 min, m/z=356.1, 358.1 [MH+].

Example 128: Synthesis of1-(4-(hydroxyamino)-6-isopropylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(187)

Step 1: 1-(4-Chloro-6-isopropylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(186)

A mixture of 4-chloro-6-isopropylpyrimidin-2-amine (181) (0.70 g, 3.78mmol) and 2-naphthyl-isocyanate (0.69 g, 3.78 mmol) in toluene (5 mL)was heated to 100° C. for 3 h. The precipitate formed was collectedthrough filtration, and washed with ether/hexanes (1:1) to give thetitle compound as a white solid (186) (0.85, 61%). LC/MS: Rt=4.1 min,m/z=341.2 [MH+]. This material was used directly in the next step.

Step 2:1-(4-(hydroxyamino)-6-isopropylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(187)

To a mixture of1-(4-chloro-6-isopropylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea (186)(0.20 g, 0.59 mmol) and hydroxylamine hydrochloride (0.42 g, 5.9 mmol)in 2-propanol (5 mL) was added triethylamine (0.33 mL, 2.3 mmol) and theresulting mixture was heated to 80° C. for 2 h. The mixture was filteredand washed with methanol to obtain the title compound (187) as a whitesolid. (0.18 g, 85%). LC/MS: Rt=2.37 min, m/z=338.2 [MH+].

Example 129: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-isopropylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(188)

Step 1:1-(4-((3-(dimethylamino)propyl)amino)-6-isopropylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(188)

To a mixture of1-(4-chloro-6-isopropylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea (186,Example 128) (0.20 g, 0.59 mmol) and 3-(dimethylamino)-1-propylamine(0.17 mL, 1.43 mmol) in 2-propanol (3 mL) was added triethylamine (0.1mL, 0.7 mmol), and the resulting mixture was heated to 80° C. for 15 h.The mixture was filtered and washed with methanol to obtain the titlecompound (188) (0.17 g, 66%) as a white solid. LC/MS: Rt=1.73 min,m/z=407.3 [MH+].

Example 130: Synthesis of1-(4-amino-6-isopropylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea (190)

Step 1:1-(4-Isopropyl-6-((4-methoxybenzyl)amino)pyrimidin-2-yl)-3-(naphthalen-2-yl)urea(189)

To a mixture of1-(4-chloro-6-isopropylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea (186,Example 128) (0.15 g, 0.44 mmol) and 4-methoxybenzylamine (0.12 mL, 0.88mmol) in 2-propanol (2 mL) was added triethylamine (0.16 mL, 1.1 mmol),and the resulting mixture was heated to 80° C. for 15 h. The mixture wasfiltered and washed with methanol to obtain the title compound (189)(0.21 g, 100%) as a white solid. The material was used directly in thenext step.

Step 2: 1-(4-Amino-6-isopropylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea(190)

To1-(4-isopropyl-6-((4-methoxybenzyl)amino)pyrimidin-2-yl)-3-(naphthalen-2-yl)urea(189) (0.21 g, 0.44 mmol) was added TFA (7 mL) and the mixture stirredvigorously and heated to 80° C. for 2 hours. The mixture wasconcentrated under reduced pressure and 10% ammonia in water added toneutralize reaction before concentration under reduced pressure. Theresidue was purified by chromatography using dichloromethane and ammoniain methanol to afford the title compound (190) (5 mg, 3%). LC/MS:Rt=0.25 min, m/z=322.2 [MH+].

Example 131: Synthesis of1-(4-isopropyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)-3-(naphthalen-2-yl)urea(192)

Step 1: tert-Butyl(3-((6-isopropyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)propyl)(methyl)carbamate(191)

To a mixture of1-(4-chloro-6-isopropylpyrimidin-2-yl)-3-(naphthalen-2-yl)urea (186,Example 129) (0.15 g, 0.44 mmol) and 3-(N-Boc-N-methylamino)propylamine(0.11 mL, 0.53 mmol) in 2-propanol (0.5 mL) was added triethylamine (0.9mL, 0.66 mmol), and the resulting mixture was heated to 80° C. for 8 h.The mixture was diluted with diethyl ether, filtered and dried to obtainthe title compound (191) as a white solid (0.14 g, 64%). The materialwas used directly in the next step.

Step 2:1-(4-Isopropyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)-3-(naphthalen-2-yl)urea(192)

tert-Butyl(3-((6-isopropyl-2-(3-(naphthalen-2-yl)ureido)pyrimidin-4-yl)amino)propyl)(methyl)carbamate(191) (0.12 g, 0.25 mmol) was suspended in dichloromethane (0.7 mL) andTFA (0.3 mL, 4.2 mmol) added. On stirring a solution formed which, after2 hours was concentrated. Saturated sodium bicarbonate solution wasadded to obtain a pH of 8. The mixture was filtered and washed withwater, ethanol and then ether to obtain the title compound (192) as awhite solid (45 g, 46%). LC/MS: Rt=1.72 min, m/z=393.3 [MH+].

Example 132: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-isopropylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(194)

Step 1:1-(4-Chloro-6-isopropylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(193)

A mixture of 4-chloro-6-isopropylpyrimidin-2-amine (0.70 g, 3.87 mmol)and 4-(trifluoromethyoxy)phenyl isocyanate (0.80 g, 3.87 mmol) intoluene (5 mL) was heated to 100° C. for 3 h. The precipitate formed wascollected through filtration, and washed with ether/hexanes (1:1) togive the title compound (193) as a yellow solid (0.78, 51%). LC/MS:Rt=4.61 min, m/z=375.1 [MH+]. The material was used directly in the nextstep.

Step 2:1-(4-((3-(Dimethylamino)propyl)amino)-6-isopropylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(194)

To a mixture of1-(4-chloro-6-isopropylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)-phenyl)urea(193) (75 mg, 0.20 mmol) and 3-(dimethylamino)-1-propylamine (0.03 mL,0.24 mmol) in 2-propanol (0.5 mL) was added triethylamine (0.04 mL, 0.3mmol), and the resulting mixture was heated to 80° C. for 1 h. Oncooling, the mixture was diluted with methanol and evaporated. Theresidue was purified by preparative TLC in 15% methanol indichloromethane to afford the product (194) (20 mg, 23%). LC/MS: Rt=1.92min, m/z=441.3 [MH+].

Example 133: Synthesis of1-(4-amino-6-isopropylpyrimidin-2-yl)-3-(4-(trifluoro-methoxy)phenyl)urea(196)

Step 1:1-(4-Isopropyl-6-((4-methoxybenzyl)amino)pyrimidin-2-yl)-3-(4-trifluoromethoxy)phenyl)urea(195)

To a mixture of1-(4-chloro-6-isopropylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(193, Example 132) (75 mg, 0.20 mmol) and 4-methoxybenzylamine (0.05 mL,0.40 mmol) in 2-propanol (0.5 mL) was added triethylamine (0.04 mL, 0.30mmol), and the resulting mixture was heated to 80° C. for 1 h. Anadditional portion of 4-methoxybenzylamine (0.03 mL) was added andheating continued. After 3 h, the mixture was diluted with methanol (3mL) and filtered to obtain the title compound as a white solid (195) (69mg, 72%). The material was used directly in the next step.

Step 2:1-(4-Amino-6-isopropylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(196)

To1-(4-isopropyl-6-((4-methoxybenzyl)amino)pyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(195) (69 mg, 0.14 mmol) was added TFA (2.5 mL) and the mixture stirredvigorously and heated to 80° C. overnight. The mixture was concentratedunder reduced pressure and saturated sodium bicarbonate added to a pH of8. The solid was filtered and purified by preparative TLC using 5%methanol in dichloromethane to afford the title compound (196) (28 mg,46%). LC/MS: Rt=2.47 min, m/z=356.2 [MH+].

Example 134: Synthesis of1-(4-isopropyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(198)

Step 1: tert-Butyl(3-((6-isopropyl-2-(3-(4-(trifluoromethoxy)phenyl)ureido)pyrimidin-4-yl)amino)propyl)(methyl)carbamate(197)

To a mixture of1-(4-chloro-6-isopropylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(193, Example 132) (75 mg, 0.20 mmol) and3-(N-Boc-N-methylamino)propylamine (0.05 g, 0.24 mmol) in 2-propanol(0.4 mL) was added triethylamine (0.04 mL, 0.3 mmol), and the resultingmixture was heated to 80° C. for 1 h. Additional3-(N-Boc-N-methylamino)propylamine (26 mg) dissolved in 2-propanol (0.2mL) was added and heating continued. After 2 h, the mixture was dilutedwith methanol, and filtered to yield a solid (5 mg). The filtrate wasconcentrated and purified by preparative TLC [5% methanol indichloromethane] to yield an additional solid identical to the initialsolid as the title compound (197) (40 mg, 37%). The material was useddirectly in the next step.

Step 2:1-(4-Isopropyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(198)

tert-Butyl(3-((6-isopropyl-2-(3-(4-(trifluoromethoxy)phenyl)ureido)pyrimidin-4-yl)amino)propyl)(methyl)carbamate(197) (40 mg, 0.075 mmol) was suspended in dichloromethane (0.06 mL) andTFA (0.06 mL, 0.75 mmol) added. On stirring a solution formed which,after 1.5 hours was concentrated. Saturated sodium bicarbonate solutionwas added to obtain a pH of 8. Upon stirring for 2 h, the mixture wasfiltered to obtain the title compound (198) as a white solid (28 mg,86%). LC/MS: Rt=1.91 min, m/z=427.2 [MH+].

Example 135: Synthesis of1-(4-(hydroxyamino)-6-isopropylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenylurea (199)

Step 1:1-(4-(Hydroxyamino)-6-isopropylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)-phenyl)urea(199)

To a mixture of1-(4-chloro-6-isopropylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(193, Example 132) (75 mg, 0.20 mmol) and hydroxylamine hydrochloride(66 mg, 2 mmol) in ethanol (0.5 mL) was added triethylamine (0.11 mL,0.8 mmol) and the resulting mixture was heated to 80° C. for 3 h. Themixture was diluted with methanol (5 mL) and filtered. The solid waspurified by preparative TLC (15% MeOH in dichloromethane) to obtain thetitle compound (199) as a white solid (10 mg, 14%). LC/MS: Rt=2.53 min,m/z=372.2 [MH+].

Example 136: Synthesis of1-(4-cyclopropyl-6-((3-(dimethylamino)propyl)amino)-pyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(204)

Step 1: 2-Amino-6-cyclopropylpyrimidin-4(5H)-one (201)

To a suspension of ethyl 3-cyclopropyl-3-oxopropionate (200:10 g, 60.8mmol) and guanidine hydrochloride (12.2 g, 122 mmol) in absolute ethanol120 mL was added sodium methoxide (25% in methanol: 6.9 g, 122 mmol).The resulting mixture was sealed in a pressure seal vessel and heated to100° C. overnight. The solvent was removed in vacuo and the resultingresidue was purified by flash chromatography (gradient, 20-80% EtOAc inhexanes; 0-18% MeOH in dichloromethane) to obtain the desired compound(201) as a pale yellow solid (7.7 g, 79%). This material was useddirectly in the next step.

Step 2: 4-Chloro-6-cyclopropylpyrimidin-2-amine (202)

2-Amino-6-cyclopropylpyrimidin-4(5H)-one (201) (7.7 g, 48.0 mmol) wastreated with phosphoryl chloride (50 mL) and this mixture heated for 4hours. The homogeneous mixture was cooled and poured onto ice. Thistemperature was maintained while adding water (500 mL) and adjustment ofthe pH to 7. The aqueous layer was extracted with ethyl acetate (3×) andthe organics washed with brine. Drying over sodium sulfate, filtrationand evaporation of the solvent yielded a solid that was chromatographedin 0-25% ethyl acetate in hexanes. The purified material wascrystallized from dichloromethane in hexanes to afford the titlecompound (202) (1.5 g, 17%). This material was used directly in the nextstep.

Step 3:1-(4-Chloro-6-cyclopropylpyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(203)

A mixture of 4-chloro-6-cyclopropylpyrimidin-2-amine (202: 0.6 g, 3.36mmol) and 3,4-dichlorophenyl-isocyanate (0.66 g, 3.36 mmol) in toluene(4 mL) was heated to 100° C. for 3 h. The precipitate formed wascollected through filtration, and washed with ether/hexanes (1:1) togive the title compound (203) as a white solid (1.02, 82%). LC/MS:Rt=4.22 min, m/z=357.0, 359.0 [MH+]. This material was used directly inthe next step.

Step 3:1-(4-Cyclopropyl-6-((3-(dimethylamino)propyl)amino)pyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(204)

To a mixture of1-(4-chloro-6-cyclopropylpyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(203) (0.2 g, 0.56 mmol) and 3-(dimethylamino)-1-propylamine (0.16 mL,1.4 mmol) in 2-propanol (3 mL) was added triethylamine (0.09 mL, 0.67mmol), and the resulting mixture was heated to 80° C. overnight. Oncooling, the mixture was filtered to afford the title compound (204)(147 mg, 59%). LC/MS: Rt=2.01 min, m/z=423.2, 425.2 [MH+].

Example 137: Synthesis of1-(4-cyclopropyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(206)

Step 1: tert-Butyl(3-((6-cyclopropyl-2-(3-(3,4-dichlorophenyl)ureido)pyrimidin-4-yl)amino)propyl)(methyl)carbamate(205)

To a mixture of1-(4-chloro-6-cyclopropylpyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(203) (0.2 g, 0.56 mmol) and 3-(N-Boc-N-methylamino)propylamine (0.14 g,0.67 mmol) in 2-propanol (1.1 mL) was added triethylamine (0.12 mL, 0.84mmol), and the resulting mixture was heated to 80° C. for 8 h. Aftercooling the mixture was diluted with ether and filtered to yield a solidproduct (205) (0.14 g, 47%). The material was used directly in the nextstep.

Step 2:1-(4-cyclopropyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(206)

tert-Butyl(3-((6-cyclopropyl-2-(3-(3,4-dichlorophenyl)ureido)pyrimidin-4-yl)amino)propyl)(methyl)carbamate(205) (0.14 g, 0.28 mmol) was suspended in dichloromethane (0.7 mL) andTFA (0.5 mL) added. On stirring a solution formed which, after 1.5 hourswas concentrated. Saturated sodium bicarbonate solution was added toobtain a pH of 8. Upon stirring for 2 h, the mixture was filtered andconcentrated. The residue was purified by chromatography [30% methanolin dichloromethane containing IN ammonia] to afford the title compound(206) (70 mg, 43%). LC/MS: Rt=2.07 min, m/z=409.1, 411.1 [MH+].

Example 138: Synthesis of1-(4-cyclopropyl-6-(hydroxyamino)pyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(207)

Step 1:1-(4-cyclopropyl-6-(hydroxyamino)pyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(207)

To a mixture of1-(4-chloro-6-cyclopropylpyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(203) (75 mg, 0.20 mmol) and hydroxylamine hydrochloride (47 mg, 0.66mmol) in 2-propanol was added triethylamine (0.12 mL, 0.84 mmol), andthe resulting mixture was heated to 80° C. overnight. The mixture wasconcentrated and purified by flash chromatography to give a solid thatwas triturated with methanol, filtered and dried to afford the titlecompound (207) (0.04 g, 5%). LC/MS: Rt=0.24 min, m/z=354.1, 356.1 [MH+].

Example 139: Synthesis of1-(4-cyclopropyl-6-((3-(dimethylamino)propyl)amino)-pyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(209)

Step 1:1-(4-Chloro-6-cyclopropylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea208)

A mixture of 4-chloro-6-cyclopropylpyrimidin-2-amine (202: 0.6 g, 3.36mmol) and 4-(trifluoromethyoxy)phenyl isocyanate (0.69 g, 3.36 mmol) intoluene (4 mL) was heated to 100° C. for 3 h. The precipitate formed wascollected through filtration, and washed with ether/hexanes (1:1) togive the title compound (208) as a white solid (0.84, 64%). LC/MS:Rt=4.03 min, m/z=373.1 [MH+]. This material was used directly in thenext step.

Step 2:1-(4-Cyclopropyl-6-((3-(dimethylamino)propyl)amino)pyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(209)

To a mixture of1-(4-chloro-6-cyclopropylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(208) (75 mg, 0.20 mmol) and 3-(dimethylamino)-1-propylamine (0.03 mL,0.24 mmol) in 2-propanol (0.5 mL) was added triethylamine (0.04 mL, 0.30mmol), and the resulting mixture was heated to 80° C. overnight. Oncooling, the mixture was concentrated and purified by preparative TLC in15% methanol in dichloromethane to afford the title compound (209) (34mg, 38%). LC/MS: Rt=2.00 min, m/z=439.2 [MH+].

Example 140: Synthesis of1-(4-cyclopropyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(211)

Step 1: tert-Butyl(3-((6-cyclopropyl-2-(3-(4-(trifluoromethoxy)phenyl)ureido)-pyrimidin-4-yl)amino)propyl)(methyl)carbamate(210)

To a mixture of1-(4-chloro-6-cyclopropylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)-phenyl)urea(208) (75 mg, 0.20 mmol) and 3-(N-Boc-N-methylamino)propylamine (48 mg,0.24 mmol) in 2-propanol (0.5 mL) was added triethylamine (0.04 mL, 0.30mmol), and the resulting mixture was heated to 80° C. overnight. Aftercooling the mixture was concentrated and purified by preparative TLC in5% methanol in dichloromethane to yield a solid product (210) (31 mg,29%). The material was used directly in the next step.

Step 2:1-(4-cyclopropyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(211)

tert-Butyl(3-((6-cyclopropyl-2-(3-(4-(trifluoromethoxy)phenyl)ureido)pyrimidin-4-yl)amino)propyl)(methyl)carbamate(210) (31 mg, 0.06 mmol) was suspended in dichloromethane (0.04 mL) andTFA (0.04 mL) were added. On stirring a solution formed which, after 3hours was concentrated. Saturated sodium bicarbonate solution was addedto obtain a pH of 8. Upon stirring for 1.5 h, the mixture was filteredto obtain the title compound (211) as a white solid (16 mg, 66%). LC/MS:Rt=2.02 min, m/z=425.2 [MH+].

Example 141: Synthesis of1-(4-cyclopropyl-6-(hydroxyamino)pyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(212)

Step 1:1-(4-cyclopropyl-6-(hydroxyamino)pyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(212)

To a mixture of1-(4-chloro-6-cyclopropylpyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(203) (75 mg, 0.20 mmol) and hydroxylamine hydrochloride (66 mg, 2.0mmol) in ethanol (0.5 mL) was added triethylamine (0.11 mL, 0.80 mmol),and the resulting mixture was heated to 80° C. After 1 hr the reactionwas cooled overnight. Heating was resumed at 80° C. for 1 hour. Themixture diluted with methanol and filtered to obtain the title compound(212) as a white solid. (28 mg, 38%). LC/MS: Rt=2.80 min, m/z=370.1[MH+].

Example 142: Solubility of Compound 174

Into a 1 dram vial was added a sample of compound 174. DI water wasadded until the solid was fully dissolved. Solubility was estimated fromthe amount of solid per mL of water added. Estimated solubility ˜30mg/mL (2 determinations).

Example 143: GBM4 and GBM8 Viability Assay

Cell culture medium was prepared from a NSA proliferation kit(Neurocult) and NeuroCult supplements (Stemcell Tech Cat. #05751) andtreated with 20 μL of 10 μg/mL rh EGF, 10 μL of 10 μg/mL rh bFGF and 10μL of 0.2% Heparin. In this medium, human glioblastoma cells werecultured in ultra-low attachment tissue culture flasks until 1×106 cellsml was achieved (GBM4 and GBM8 are distinct neurosphere cell culturesderived from these human patient tissues). GBM4 and GBM8 cells weredissociated and 10 mL of media containing 4000 human glioblastoma cellsper 90 uL were transferred to an ultra-low binding 96-well plate andincubated at 37° C. overnight. On the following day, 10 μL of a 1% DMSOsolution of test compound in assay medium was added to wells containingthe cell suspension and the mixture incubated at 37° C. for 3 days. Atthis time, the plate was removed from the incubator and allowed to reachroom temperature. After about 30 minutes, 50 μL of Cell Titer Glosolution was added to each well and the plate shaken for 1 minute at lowspeed. After 10 minutes luminescence was recorded using a Tecan Safire2reader.

Reduction in luminescence compared to DMSO only control wells was usedto determine the percentage inhibition of cell growth. IC50s werecalculated using the % inhibition of luminescence for serial dilutionsof compounds fitted to a 4-parameter fit within the Prism (San Diego)curve fitting program. Tables 1 (compounds 3-188) and 2 (compounds190-212) show the GBM4 IC50 and GBM8 IC50 for compounds describedherein.

TABLE 1 GBM4 IC50 GBM8 IC50 Cpd # (uM) (uM) 3 A A 4 A A 5 NT A 6 NT A 7A A 8 NT A 9 NT B 10 NT A 11 NT B 12 NT A 13 NT A 14 NT A 15 NT C 16 NTA 17 NT A 18 NT A 19 NT A 20 NT A 21 NT B 22 NT A 23 NT A 24 NT A 25 NTA 26 NT A 27 NT A 28 NT A 30 NT A 31 NT A 32 NT A 33 NT A 34 NT A 35 NTA 36 NT A 37 NT A 38 NT B 42 NT B 43 NT A 44 NT A 45 NT A 47 NT A 50 NTA 51 NT B 52 NT B 53 NT B 54 NT A 55 NT A 56 NT A 57 NT A 58 NT A 59 NTB 60 NT A 61 NT A 62 NT A 64 NT A 65 NT A 66 NT A 67 NT A 71 NT A 75 NTA 76 NT B 77 NT A 80 NT A 81 NT A 82 NT A 83 NT A 84 NT A 85 NT A 86 NTA 89 NT C 90 NT B 91 NT B 92 NT B 93 NT B 96 NT B 97 NT C 98 NT B 99 NTB 100 NT B 101 NT B 102 NT B 105 NT B 106 NT B 107 NT B 108 NT B 109 NTB 110 NT B 111 NT A 114 NT A 115 NT B 116 NT B 117 NT B 118 NT A 119 NTB 120 NT A 123 NT A 125 NT A 126 NT A 128 NT B 131 NT B 133 NT A 134 NTA 136 NT A 137 NT A 139 NT A 140 NT A 142 NT A 144 NT A 145 NT A 146 NTB 147 NT A 149 NT A 150 NT A 151 NT A 153 NT A 155 NT A 157 NT B 158 NTB 160 NT A 161 NT B 162 NT A 163 NT B 168 NT B 170 NT NT 172 NT NT 174NT A 176 NT A 184 NT B 185 NT B 187 NT B 188 NT B IC50: A < 0.5 μM; 0.5μM ≤ B ≤ 5 μM; 5 μM < C ≤ 30 μM; NT = not tested

TABLE 2 GBM4 IC50 GBM8 IC50 Cpd # (uM) (uM) 190 NT C 192 NT B 194 NT B196 NT B 198 NT B 199 NT B 204 NT B 206 NT C 207 NT B 209 NT B 211 NT B212 NT B IC50: A < 0.5 μM; 0.5 μM ≤ B ≤ 5 μM; 5 μM < C ≤ 30 μM; NT = nottested

Example 144: Depletion of Olig2 in Glioblastoma Cells Measured byWestern

GBM cells (10⁻⁶/plate well) treated with olig2 inhibitors at varyingconcentrations were transferred to epitubes and lysed with Ripa buffer(30-35 μL) containing inhibitors. Lysate concentrations were determinedusing Pierce Coumassie Plus per instructions. Protein Simple Wesreagents, DTT, Fluorescent 5× Master Mix, Biotinylated ladder and 10×Sample Buffer, were prepared per manufacturer's instructions.

Lysate samples were prepared for western analysis at a finalconcentration of 0.4 mg/ml. Lysates were diluted with 0.1× Sample Buffer(diluted 10× Sample Buffer 1:100 with water). 1 part 5× FluorescentMaster Mix was combined with 4 parts lysate in a microfuge tube, finalconcentration 0.4 mg/ml. Samples and Biotinylated Ladder were denaturedfor 5 minutes at 95° C. and then centrifuged. Protein Simple plates wereloaded with lysate samples, dilution buffers, diluted antibodies Olig2and GAPDH, and luminal reagent per manufacturer's instructions. IC₅₀values were calculated based on changes in band density normalized tointernal controls.

IC₅₀ values for Olig2 depletion in GBM4 and GBM8 cells are shown inTable 3.

TABLE 3 Compound GBM4 IC₅₀ GBM4 IC₅₀ GBM8 IC₅₀ Number (Cytotoxicity)(Olig 2 Depletion) (Olig 2 Depletion) 19 0.06 0.04 35 0.14 0.13 36 0.040.03 174 0.24 0.18 0.13 176 0.01

Example 145: Tumor Growth Inhibition of Olig2 Inhibitors in Mouse FlankTumor Models

Female NSG mice (NOD.Cg-Prkdc^(scid) Il2rg^(tm1Wj1)/SzJ, The JacksonLaboratory) were six weeks old on Day 1 of the study and had a bodyweight range of 17.8 g to 22.7 g. The animals were fed ad libitum water(reverse osmosis, 1 ppm Cl) and NIH 31 Modified and Irradiated Lab Diet®consisting of 18.0% crude protein, 5.0% crude fat, and 5.0% crude fiber.The mice were housed on irradiated Enrich-o'Cobs™ bedding in staticmicroisolators on a 12-hour light cycle at 20-22° C. (68-72° F.) and40-60% humidity.

Human GBM4 or GBM8 glioblastoma cell lines were maintained in CompleteNeuroCult Proliferation Medium containing 20 ng/mL EGF, 10 ng/mL bFGFand 2 μg/mL Heparin. The cells were cultured in ultra low attachment T75flask (Corning REF-3814) and the resulting neurospheres were dissociatedevery 4-6 days using the NeuroCult Chemical Dissociation kit (StemcellTechnologies Cat #05707). Cell cultures were maintained in tissueculture flasks in a humidified incubator at 37° C., in an atmosphere of5% CO₂ and 95% air. Cell samples were collected one passage prior tocell implant and preserved in freezing media.

Cells used for implantation were harvested during log phase growth andresuspended in cold PBS containing in 50% Matrigel™ (BD Biosciences).Tumor growth was initiated on Day 1 by subcutaneous injection of GBM4cells into the right flank of each mouse with 1×10⁷ tumor cells (0.1 mLcell suspension) and tumor growth was monitored in four groups (n=8)beginning on Day 12. Groups for treatment included group 1 (vehicle),group 2 (test Olig2 inhibitor), group 3 (treatment with temozolomide andradiation) and group 4 (test Olig2 inhibitor combined with temozolomideand radiation). The tumors were measured with a caliper in twodimensions to monitor size. Tumor size was calculated using the formula:Tumor Volume (mm³)=w²×½; where w=width and 1=length, in mm, of a tumor.Tumor weight may be estimated with the assumption that 1 mg isequivalent to 1 mm³ of tumor volume. Tumors were measured with a calipertwice weekly for the duration of the study. Temozolomide (Merck & Co.,Lot No. L046487) was administered orally at doses of 5 mg/kg or 10mg/Kg). Radiation was adminstered with a Faxitron model CP-160 X-raysystem. Each animal was immobilized in a live restrainer. Therapy wasadministered for 1.3 min at 160 kV and 6.0 mA, providing a dose of 1gray (Gy) for each animal.

The study endpoint was a tumor volume of 2000 mm³ or Day 152, whichevercame first. Each animal was euthanized for tumor progression (TP) whenits tumor reached the volume endpoint. The time to endpoint (TTE) foreach animal was calculated with the following equation:

TTE (days)=log₁₀(endpoint volume, mm³)-b/m; where b is the intercept andm is the slope of the line obtained by linear regression oflog-transformed tumor growth data set.

The data set is comprised of the first observation that exceeded thestudy endpoint volume and the three consecutive observations thatimmediately preceded the attainment of the endpoint volume. Any animalthat did not reach endpoint was euthanized at the end of the study andassigned a TTE value equal to the last day of the study (Day 152). Ininstances in which the log-transformed calculated TTE preceded the dayprior to reaching endpoint or exceeded the day of reaching tumor volumeendpoint, a linear interpolation was performed to approximate the TTE.Any animal determined to have died from treatment-related (TR) causeswas assigned a TTE value equal to the day of death. Any animal that diedfrom non-treatment-related (NTR) causes was excluded from analysis.

Treatment outcome was evaluated from tumor growth delay (TGD), which wasdefined as the increase in the median TTE for a treatment group comparedto the control group:TGD=T−C,expressed in days, or as a percentage of the median TTE of the controlgroup:TGD(%)=T−C/C×100T=median TTE for a treatment group,C=median TTE for the control group.

Example compounds show a significant delay (TGD) in TTE eitheradministered alone (group 2 treatments) and increased TTE when combinedwith temozolomide and radiation (group 4). Delay to TTE is increasedrelative to temozolomide and radiation alone (group 3).

Data for tumor growth inhibition (median TTE) in GBM4 and GBM8 cells areshown in the Table 4.

TABLE 4 Compound + Vehicle Temozolomide + Compound Temozolomide +Compound Cell (median radiation (median radiation Number line TTE)(median TTE) TTE) (median TTE) 174 GBM4 48.3 116.3 73.0 152.0 174 GMB841.4 86.2 61.3 >140.0 176 GMB8 48.6 78 56.4 127.9

Example 146: Survival of Olig2 Inhibitors in Orthotopic GlioblstomaMouse Models

Patient-derived xenograft samples were used in this study as a morefaithful representation of human glioblastoma compared to immortalizedcell lines. The maintenance of patient-derived xenografts exclusively byserial passage in mice has been advocated as a means to faithfullypreserve the genetic features of the original tumors. Tumor integrity isperiodically confirmed by short tandem repeat assessment. These methodswere used to obtain cell suspensions of G06 cells for use in vivo.Briefly, short-term cultured cells were injected into the flank ofathymic nude mice (Nu/Nu: Envigo). Tumors grown in these mice wereharvested and cultured to afford cell suspension for viability studies.Mice with tumors 1-1.5 cm³ were euthanized using CO₂. Tumors wereswabbed with Betadine (Carefusion #29906-016) and excised with a sterilescalpel. The tumor sample was placed in a culture plate and broken upwith a sterile syringe. Stem Cell Media prepared from a kit (StemPro NSCSFM kit: ThermoFisher Scientific #A1050901: 3 mL) was added. [To make500 mL, the following components plus L-glutamine and Pen-Strep solutionwere combined as follows and filtered sterilized (Nalgene: ThermoScientific #156-4020): KnockOut DMEM/F-12 Basal Media-500 mL; StemProNSC SFM Supplement-10 mL; FGF Basic Recombinant Human-10 μg; EGFRecombinant Human-10 μg; L-glutamine (Corning #25005CI): 10 mL of 200 mMsolution and Penicillin/Streptomycin (Corning #30001CI; 5000 I.U./mLPen, 5000 [μg/mL strep (P/S) 5 ml]. Cell suspensions were evenlydistributed into laminin (Sigma #L2020-1MG)-coated flasks (Corning#430825) and additional media added (25-35 mL). Cells were maintained inan incubator (37° C., 5% CO₂) until adherence to flasks was complete(1-7 days). Debris was removed; media replenished and cells werecultured to 80-90% confluence. At this time, cells were trypsinizedusing Trypsin-EDTA (Corning #25-052-CI; 0.05% trypsin/0.53 mM EDTA inHBSS). After completion trypsin was neutralized with DMEM (10% FBS and1% P/S: 10-20 mL) (Corning #10-013-CV). Cells and media were centrifugedat 320RCF for 3 minutes. The pellets were resuspended in Stem Cell Mediato a concentration of 10⁵ cells/100 μL as measured by a hemocytometer.

G06 or cultured GBM8 cells (3×10⁵, 3 μL), were injected intracraniallyinto anesthetized female athymic nude mice (Nu/Nu: Envigo). Uponrecovery, mice were randomized into groups of 8 mice: one receivingvehicle and others receiving ascending oral dose of example compounds.Formulations were administered at 200 μL/20 g based on mouse weight tothe treatment group daily beginning day 4 after cell implantation.Administration was continued until mice were moribund or dead. Animalcounts and body weight were monitored daily. Survival improvement wasmeasured as a percent increase of the median for drug treatment versusvehicle. Example compounds demonstrate a statistically significantimprovement in median survival.

Efficacy data (estimated GBM survival benefit) for Compounds 174 and 176are shown in Table 5.

TABLE 5 G06: Estimated Median GBM8: Estimated Median Compound SurvivalBenefit (%) Survival Benefit (%) 174 54 48 176 46 72

Example 147: Phase II Clinical Trial of Compounds of Formula (I), (II),(III), or (IV) in Patients with Recurrent Rb Positive Glioblastoma

The purpose of this phase II trial is to determine the efficacy of acompound of Formula (I), (II), (III), or (IV) (as measured byprogression free survival at 6 months) in patients with recurrentglioblastoma multiforme or gliosarcoma who are Rb positive. A total of30 patients will be treated; 15 will undergo a planned surgicalresection and receive drug for 7 days prior to surgery, followed by drugafter recovery from surgery, and the other 15 patients will receive drugwithout a planned surgical procedure.

Patients:

Eligible subjects will be men and women 18 years and older

Criteria:

Inclusion Criteria:

-   -   Patients with radiographically proven recurrent, intracranial        Glioblastoma multiforme or Gliosarcoma will be eligible for this        protocol. Patients must have documentation of Rb positive        disease.    -   All patients must sign an informed consent indicating that they        are aware of the investigational nature of this study. Patients        must have signed an authorization for the release of their        protected health information. Patients must be registered prior        to treatment with study drug. Treatment must take place within 7        days of registration; if treatment is delayed more than 7 days,        the laboratory tests for eligibility and history and physical        exam must be repeated.    -   Patients must have had prior external beam radiation and        temozolomide chemotherapy; there is no limit to the number of        prior chemotherapies used; patients may be treated in their        first, second or third relapse    -   Patients must be >18 years old, and with a life expectancy >8        weeks.    -   Patients must have a Karnofsky Performance Status of >60.    -   At the time of registration: Patients must have recovered from        the toxic effects of prior therapy: >28 days from any        investigational agent [NOTE: off-label use of FDA approved        agents are not considered investigational for the purposes of        this protocol], >28 days from prior cytotoxic therapy, >42 days        from nitrosoureas, >28 days from bevacizumab, and >7 days for        non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide,        cis-retinoic acid, and erlotinib, for example. Any questions        related to the definition of non-cytotoxic agents should be        directed to the Study Chair.    -   Patients must have adequate bone marrow function (WBC >3,000/μl,        ANC >1,500/mm3, platelet count of >100,000/mm3, and        hemoglobin >10 gm/dl), adequate liver function (SGOT and        bilirubin <2 times ULN), and adequate renal function (creatinine        <1.5 mg/dL) before starting therapy. A pre-study EKG is required        for all patients, and patients must have a normal QT interval.        These tests must be performed within 14 days prior to        registration. Eligibility level for hemoglobin may be reached by        transfusion.    -   Patients must have shown unequivocal radiographic evidence for        tumor progression by MRI scan. A scan should be performed within        14 days prior to registration and on a steroid dose that has        been stable for at least 7 days. If the steroid dose is        increased between the date of imaging and registration a new        baseline MRI is required. The same type of scan, i.e., MRI must        be used throughout the period of protocol treatment for tumor        measurement. Patients unable to undergo MR imaging will not be        eligible.    -   Patients having undergone recent resection of recurrent or        progressive tumor will be eligible as long as all of the        following conditions apply:        -   They have recovered from the effects of surgery.        -   Residual disease following resection of recurrent            intracranial Glioblastoma Multiforme or Gliosarcoma is not            mandated for eligibility into the study. To best assess the            extent of residual disease post-operatively, an MRI should            be done no later than 96 hours in the immediate            post-operative period or at least 4 weeks post-operatively,            within 14 days prior to registration. If the 96-hour scan is            more than 14 days before registration, the scan needs to be            repeated. If the steroid dose is increased between the date            of imaging and registration, a new baseline MRI is required            on a stable steroid dosage for at least 7 days.    -   Patients must have failed prior radiation therapy and        temozolomide and must have an interval of greater than or equal        to 42 days from the completion of radiation therapy to study        entry.    -   Patients with prior therapy that included interstitial        brachytherapy, stereotactic radiosurgery, or Gliadel wafers must        have confirmation of true progressive disease rather than        radiation necrosis based upon PET scanning, MR spectroscopy or        surgical documentation of disease.    -   A subset of 15 patients will be enrolled prior to a planned,        indicated surgical resection. Patients can be enrolled        pre-operatively only if they are surgical candidates, do not        have evidence of an acute intracranial hemorrhage and are able        to start protocol treatment in a window of 7 days before        surgery.    -   Male and female patients with reproductive potential must use an        approved contraceptive method, if appropriate (for example,        intrauterine device [IUD], birth control pills, or barrier        device) during and for 3 months after discontinuation of study        treatment. Women of childbearing potential must have a negative        beta-HCG pregnancy test documented within 14 days prior to        registration.    -   Blocks or slides of tumor tissue from a previous surgery must be        available to do IHC Rb staining. Patients with negative tumors        (Rb negative) will be excluded from the study.

Exclusion Criteria:

-   -   Patients must not have any significant medical illnesses that in        the investigator's opinion cannot be adequately controlled with        appropriate therapy or would compromise the patient's ability to        tolerate this therapy.    -   Patients with a history of any other cancer (except non-melanoma        skin cancer or carcinoma in-situ of the cervix), unless in        complete remission and off of all therapy for that disease for a        minimum of 3 years are ineligible.    -   Patients must not have an active infection or serious        intercurrent medical illness. Patients with a history of acute        intracranial hemorrhage will also be excluded.    -   Patients must not be pregnant/breast feeding and must agree to        practice adequate contraception.    -   Patients must not have any disease that will obscure toxicity or        dangerously alter drug metabolism.    -   Because of the potential for drug interactions, patients on        enzyme-inducing anti-epileptic drugs or other drugs that cause        CYP3A enzyme induction or inhibition will not be eligible unless        they are off therapy for at least 14 days    -   Patients with congenital or other reasons for prolongation of        the QT interval on EKG will be excluded.

Study Design:

A total of 30 patients with recurrent Glioblastoma or Gliosarcoma willbe treated with a compound of Formula (I), (II), (III), or (IV) at adose of 125 mg daily for 21 consecutive days followed by a 7 day breakoff therapy (cycle length is 28 days). Of these 30 patients, 15 willreceive drug for 7 days prior to an indicated, intended surgicalresection for progression, and will then resume drug at the same doseafter recovery from surgery. Treatment will be repeated every 28 days,and in the absence of disease progression patients may receive treatmentfor 12 cycles. At that time patients will be given the option tocontinue on study past 12 cycles, up to a maximum of 24 cycles.

Following registration, available blocks or slides from a previoussurgery must be submitted for diagnosis review (confirmation ofGlioblastoma multiforme or Gliosarcoma) and Rb status determination.Only patients with Rb positive tumors can be treated, and Rb tumorstatus must be known prior to any treatment. Additional tissue fromprevious surgeries will also be obtained to evaluate molecularabnormalities in the tumor. These studies will be done retrospectivelyand are not required to be performed prior to registration.

Monitoring will include a clinical and neurological exam before thebeginning of each cycle (every 4 weeks). Complete blood counts withdifferential will be examined on days 1 and 15 of each cycle. Liver andrenal function will be performed every 4 weeks. Toxicity and dosemodifications will be based on the NCI CTCAE Version 4. Disease statuswill be assessed clinically each cycle (every 4 weeks) andradiographically after each second cycle (every 8 weeks).

Primary Outcome Measures:

-   -   Efficacy as determined by progression free survival [Time Frame:        1-2 years] [Designated as safety issue: No]    -   Determine the efficacy of a compound of Formula (I), (II),        (III), or (IV) in patients with recurrent glioblastoma        multiforme or gliosarcoma who are Rb positive, as measured by        progression free survival at 6 months. A total of 30 patients        will be treated; 15 who will undergo a planned, intended        surgical resection will receive drug for 7 days prior to        surgery, followed by drug after recovery from surgery, and 15        patients who receive drug without a planned surgical procedure

Secondary Outcome Measures:

-   -   Number of Participants with Adverse Events as a Measure of        Safety and Tolerability [Time Frame: 1-2 years] [Designated as        safety issue: Yes]

Example 146: Phase II Clinical Trial of the Safety and Efficacy ofCompounds of Formula (I), (II), (III), or (IV) in Adults with Recurrentor Refractory Medulloblastoma

The purpose of this phase II trial is to how well a compound of Formula(I), (II), (III), or (IV) works in treating adult patients withrecurrent or refractory medulloblastoma.

Patients: Eligible subjects will be men and women 22 years and older.

Criteria:

Inclusion Criteria:

-   -   Patients with a histologically confirmed diagnosis of        medulloblastoma (including posterior fossa PNET) that is        recurrent, progressive, or refractory to standard therapy and        for which there is no known curative therapy are eligible; there        must be evidence of residual measurable disease or lesion in        pre-study MRI as described in section; patients with spinal        disease that is measurable will be eligible    -   The diagnosis should be confirmed at the treating institution        and tissue (either from the diagnosis or relapse or preferably        from both time points) must be available for biological studies    -   Patients with neurological deficits should have deficits that        are stable for a minimum of 1 week prior to registration; this        is to be documented in the database    -   Eastern Cooperative Oncology Group (ECOG) performance status 0-2    -   No other myelosuppressive chemotherapy or immunotherapy within 4        weeks prior to study entry (6 weeks if prior nitrosourea)    -   Decadron dose should also be stable or decreasing for at least 1        week (7 days) prior to starting therapy    -   Radiation therapy (XRT)>=3 months prior to study entry for        craniospinal irradiation (>=23 Gy); >=8 weeks for local        irradiation to primary tumor; >=2 weeks prior to study entry for        focal irradiation for symptomatic metastatic sites    -   Off all colony stimulating factors >=1 week prior to study entry        (GCSF, GM CSF, erythropoietin)    -   Absolute neutrophil count (ANC)>=1000/μL    -   Platelet count ≥=50,000/uL (transfusion independent)    -   Hemoglobin >=8.0 gm/dL (may receive RBC transfusions)    -   Creatinine clearance or radio-isotope GFR >=70 ml/min/1.73 m2 or    -   A serum creatinine=<2.0 mg/dL    -   Total bilirubin=<1.5× upper limit of normal (ULN) for age    -   Serum glutamic pyruvic transaminase (SGPT) (alanine        aminotransferase [ALT])=<2.5× institutional ULN    -   Serum glutamic-oxalacetic transaminase (SGOT) (aspartate        aminotransferase [AST])=<2.5 times institutional ULN    -   Serum albumin >=2.5 g/dL    -   Patient must have recovered from the significant acute        toxicities of all prior therapy before entering this study and        meet all other eligibility criteria    -   Pregnancy should be avoided for 12 months after the last dose        for females of child-bearing potential; female patients of        childbearing potential must not be pregnant or breast-feeding;        female patients of childbearing potential must have a negative        serum or urine pregnancy test within 24 hours prior to beginning        treatment    -   Women of childbearing potential are required to use 2 forms of        acceptable contraception, including one barrier method during        participation in the study and for the 12 months following the        last dose; for medical or personal reasons, 100% commitment to        abstinence is considered an acceptable form of birth control.        All patients should receive contraceptive counseling either by        the investigator, or by an OB/gynecologist or other physician        who is qualified in this area of expertise    -   Signed informed consent according to institutional guidelines        must be obtained

Exclusion Criteria:

-   -   Patients with any clinically significant unrelated systemic        illness (serious infections or significant cardiac, pulmonary,        hepatic or other organ dysfunction), that would compromise the        patient's ability to tolerate protocol therapy or would likely        interfere with the study procedures or results    -   Patients receiving any other anticancer or investigational drug        therapy    -   Patients with inability to return for follow-up visits or obtain        follow-up studies required to assess toxicity to therapy    -   Life expectancy <12 weeks as determined by treating physician    -   Inability to swallow capsules    -   Malabsorption syndrome or other condition that would interfere        with enteral absorption    -   History of congestive heart failure    -   History of ventricular arrhythmia requiring medication    -   Uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or        hypokalemia defined as less than the lower limit of normal for        the institution despite adequate electrolyte supplementation    -   Congenital long QT syndrome

Study Design:

Patients receive a compound of Formula (I), (II), (III), or (IV) PO oncedaily on days 1-28. Treatment repeats every 28 days for up to 26 coursesin the absence of disease progression or unacceptable toxicity.

Primary Outcomes:

-   -   Objective response rates (PR and CR) graded using RECIST        criteria [Time Frame: Up to 12 months] [Designated as safety        issue: No]    -   Ninety-five percent confidence interval estimates of the true,        unknown objective response rate will be constructed for each of        the three strata. The proportions of patients with confirmed        complete responses, partial responses and stable disease will be        reported descriptively for each of the three strata. Cumulative        incidence functions of time to objective response will also be        provided.

Secondary Outcomes:

-   -   Duration of sustained objective response [Time Frame: From the        initial scan documenting complete or partial response that was        subsequently confirmed until the earlier of documented        progression or death on study, assessed up to 12 months]        [Designated as safety issue: No]    -   Progression-free survival [Time Frame: From the date of initial        treatment with a compound of Formula (I), (II), (III), or (IV)        until the earliest of progression or death on study, assessed up        to 12 months] [Designated as safety issue: No]    -   Medical costs during the first 6 months after transplantation    -   Patient and graft survival

Example 148: Phase I/II Clinical Trial of the Safety, Tolerability, andAnti-Tumor Efficacy of Compounds of Formula (I), (II), (III), or (IV) inthe Treatment of Recurrent Malignant Astrocytomas

This is a single-center, open-label, non-randomized, Phase I/IIa studyto investigate the safety, tolerability, and antitumor efficacy of acompound of Formula (I), (II), (III), or (IV) in patients with recurrentmalignant astrocytomas (glioblastoma, gliosarcoma, anaplasticastrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma,and anaplastic ependymoma). Patients will be treated for up to 5 cycles.A treatment cycle is defined as 28 days +7 days rest (28+7 days duringcycle 1 to 4, and 28 days during cycle 5). The following cycle will notbe started until the treatment continuation criteria are fulfilled.Concomitant supportive therapies will be allowed.

Patients: Eligible subjects will be men and women ages 18 and older

Criteria:

Inclusion Criteria:

-   -   Be informed of the nature of the study and have provided written        informed consent    -   At least 18 years of age    -   ECOG performance of 0, 1, or 2, or KPS (Karnofsky performance        status)≥60.    -   Pathological verification of a WHO grade 4 astrocytoma        (glioblastoma or gliosarcoma), or WHO Grade 3 anaplastic        astrocytoma, anaplastic oligodendroglioma, anaplastic        oligoastrocytoma, or anaplastic ependymoma.    -   Documented recurrent glioblastoma, gliosarcoma, anaplastic        astrocytoma, anaplastic oligodendroglioma, anaplastic        oligoastrocytoma, or anaplastic ependymoma after at least one        failed treatment of chemotherapy and radiation    -   Expected survival of at least 3 months    -   At least 2-weeks from cytoreductive surgery, if performed,        4-weeks from bevacizumab or other chemotherapy (6-weeks if prior        chemotherapy was nitrosourea) and 12-weeks from completion of        radiotherapy.    -   Ability to undergo MRI scanning without and with imaging dye on        a periodic basis as defined in the protocol    -   At least seven (7) days off of medications with induce CYP2C9        and CYP3A4 before administration of the first dose of a compound        of Formula (I), (II), (III), or (IV)    -   Preserved major organ functions, i.e: Blood leukocyte count        ≥3.0×109/L Blood absolute neutrophil count ≥1.5×109/L Blood        platelet count ≥100×109/L Blood hemoglobin ≥100 g/L        (transfusions are allowed) Plasma total bilirubin level <1.5        times the upper institutional limit (ULN) of the ∥normal∥ (i.e.        reference) range Plasma AST (aspartate aminotransferase) or        ALT≤2.5 times upper institutional limit (ULN) of the ∥normal∥        range Plasma creatinine <1.5 times upper institutional limit        (ULN) of the ∥normal∥ range 12-lead ECG with normal tracings; or        changes that are not clinically significant and do not require        medical intervention, and QTc<500 ms At least seven (7) days off        of medications which inhibit or induce CYP2C9 or CYP3A4 before        first study treatment day.        Exclusion Criteria:    -   Ongoing infection or other major recent or ongoing disease that,        according to the Investigator, poses an unacceptable risk to the        patient    -   Grade 3 or higher constipation within the past 28 days or grade        2 constipation within the past 14 days before randomization.        (Patients with grade 2 constipation within the past 14 days        could be re-screened if constipation decreases to ≤grade 1 with        optimal management of constipation.)    -   Coexisting uncontrolled medical condition, including, but not        limited to, active cardiac disease and significant dementia    -   Hepatitis B or Hepatitis C, or HIV infection requiring        anti-retroviral therapy    -   Active malignancy other than basal cell skin cancer    -   Other active malignancy during the previous 3 years    -   Major surgical procedure within 4 weeks    -   Prior stereotactic or gamma knife radiosurgery or proton        radiation, unless unequivocal progression by functional        neuro-imaging (PET, dynamic MRI, MRS, SPECT) or by re-operation        with documented histologic confirmation of recurrence.    -   Prior anti-tumor therapy, as follows: at least 12-weeks from        radiation therapy; at least 4-weeks from prior treatment with        temozolomide or bevacizumab, 6-weeks from BCNU or CCNU.    -   Women of child bearing potential (WOCBP) who do not consent to        using acceptable methods of birth control (oral contraceptives,        IUD). For purposes of this study, WOCBP include any female who        has experienced menarche, who has not undergone tubal ligation,        and who is not postmenopausal. Post menopause is defined as:        amenorrhea ≥12 consecutive months without another cause.    -   Medically uncontrolled Type 1 or Type 2 diabetes mellitus    -   Pregnancy or lactation    -   Current participation in any other investigational clinical        trial within 4-weeks.    -   Eastern Cooperative Oncology Group (ECOG) performance status >2        after optimization of medications (See Appendix 4) or KPS <60    -   Anticipated Life expectancy less than 3 months    -   Contraindications to the investigational product or known or        suspected hypersensitivity    -   Patients who must take concomitant medications which induce or        are potent inhibitors of CYP2C9 or sensitive substrates of        CYP3A4 with narrow therapeutic range may not participate    -   Lack of suitability for participation in the trial, for any        reason, as judged by the Investigator

Study Design:

The trial will be divided in two phases. In the first phase, 10-20patients will be enrolled and treated with 300-520 mg BID of a compoundof Formula (I), (II), (III), or (IV) for 28 days. The primary endpointof the first phase is to determine the recommended Phase 2 dose (RP2D)of the compound of Formula (I), (II), (III), or (IV) in patients withrecurrent or progressive glioblastoma and to assess the safety andtoxicity of the compound of Formula (I), (II), (III), or (IV) in thispatient population. The study has a 3+3 design and the first cohort willbe treated with 400 mg a compound of Formula (I), (II), (III), or (IV)BID for 28 days repeated in up to 5 cycles. If dose-limiting toxicity(DLT) such as neutropenia occurs, dosing will be interrupted and theindividual patient will, following normalization, be restarted on thesame or a lower dose level according to standardized procedure. If twoor three of the first 3 patients on a specific dose level experience aDLT during the first 28 days of treatment with the compound of Formula(I), (II), (III), or (IV), the following patients will be treated with alower dose level. If one DLT occurs during the first 28 days of dosingin the first 3 three patients another 3 patients will be treated withthe same dose level. If 2 of the 6 patients display DLT, the nextpatients will be treated with a lower dose level. The highest dose levelwithout DLT or with maximally one DLT out of 6 patients will be theRPTD. All assessments with respect to dose adjustments for subsequentcohorts will be done during the first 28 days of treatment.Non-progressing patients may be treated for a total of five 28-daycycles (24 weeks).

In the second phase, 12 patients will be enrolled and treated with theidentified RP2D of the compound of Formula (I), (II), (III), or (IV) for28 days repeated in five cycles. The primary endpoints of phase II is toassess the proportion of patients who are progression-free at 24 weeksand to assess safety, tolerability, and adverse event profile of thecompound of Formula (I), (II), (III), or (IV).

Primary Outcomes:

-   -   Phase I—Determine recommended Phase II dose. [Time Frame: 8        months] [Designated as safety issue: Yes]    -   Phase II—Determine Antitumor effect [Time Frame: 4 months]        [Designated as safety issue: Yes]    -   Phase I—Number of Participants with Adverse Events as a Measure        of Safety and Tolerability [Time Frame: 6 months] [Designated as        safety issue: Yes]        -   physical/neurological examinations (pathological findings            and quality and quantity)        -   adverse events (quality and quantity per dose level)        -   vital signs, ECG, laboratory parameters (pathological            findings as quality and quantity, for laboratory parameters,            descriptive statistics)

Secondary Outcomes:

-   -   Renal Phase I—Maximum Tolerated Dose (MTD) [Time Frame: 8        months] [Designated as safety issue: Yes]    -   To identify the MTD of a compound of Formula (I), (II), (III),        or (IV).    -   Phase I—Molecular markers of optimum response [Time Frame: 8        months] [Designated as safety issue: Yes]    -   To assess potential molecular markers that might predict optimum        response sub-population groups    -   Phase I—Molecular Markers of IGF (insulin like growth factor)-1R        pathway [Time Frame: 8 months] [Designated as safety issue: Yes]    -   To evaluate surrogate molecular markers of IGF-1R pathway        activation/inhibition after treatment with the compound of        Formula (I), (II), (III), or (IV) in patients with malignant        astrocytomas    -   Phase II—Time-To-Progression (TTP) and Overall Survival (OS)        [Time Frame: 4 months] [Designated as safety issue: Yes]    -   To determine time-to-progression (TTP) and overall survival (OS)        of patients treated with the compound of Formula (I), (II),        (III), or (IV)    -   Phase II—Overall Response Rate [Time Frame: 4 months]        [Designated as safety issue: Yes]    -   To assess overall response rate (ORR) in recurrent malignant        astrocytomas after treatment with the compound of Formula (I),        (II), (III), or (IV)    -   Phase II—Imaging Evidence of Response. [Time Frame: 4 months]        [Designated as safety issue: Yes]    -   To identify surrogate imaging evidence of response on MRI        (magnetic resonance imaging) sequences by RANO criteria (with        additional special attention to T2-FLAIR, DWI        (diffusion-weighted imaging), perfusion MRI and multi-voxel MRS        (magnetic resonance spectroscopy) sequences).

Example 149: Pharmaceutical Compositions Example 149A: ParenteralComposition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a compound of Formula (I), (II),(III), or (IV) is dissolved in DMSO and then mixed with 10 mL of 0.9%sterile saline. The mixture is incorporated into a dosage unit formsuitable for administration by injection.

In another embodiment, the following ingredients are mixed to form aninjectable formulation:

Ingredient Amount Compound of Formula (I), (II), (III), or (IV) 1.2 gsodium acetate buffer solution (0.4M) 2.0 mL HCl (1N)or NaOH (1M) q.s.to suitable pH water (distilled, sterile) q.s.to 20 mL

All of the above ingredients, except water, are combined and stirred andif necessary, with slight heating if necessary. A sufficient quantity ofwater is then added.

Example 149B: Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula (I), (II), (III), or (IV) is mixed with 750 mg ofstarch. The mixture is incorporated into an oral dosage unit, such as ahard gelatin capsule, which is suitable for oral administration.

In another embodiment, the following ingredients are mixed intimatelyand pressed into single scored tablets.

Ingredient Quantity per tablet, mg compound of Formula (I), (II), (III),or (IV) 200 Cornstarch 50 croscarmellose sodium 25 Lactose 120 magnesiumstearate 5

In yet another embodiment, the following ingredients are mixedintimately and loaded into a hard-shell gelatin capsule.

Ingredient Quantity per tablet, mg compound of Formula (I), (II), (III),or (IV) 200 lactose, spray-dried 148 magnesium stearate 2

In yet another embodiment, the following ingredients are mixed to form asolution/suspension for oral administration:

Ingredient Amount Compound of Formula (I), (II), (III), or (IV) 1 gAnhydrous Sodium Carbonate 0.1 g Ethanol (200 proof), USP 10 mL PurifiedWater, USP 90 mL Aspartame 0.003 g

Example 149C: Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound of Formula (I), (II), (III), or(IV) with 420 mg of powdered sugar mixed with 1.6 mL of light cornsyrup, 2.4 mL distilled water, and 0.42 mL mint extract. The mixture isgently blended and poured into a mold to form a lozenge suitable forbuccal administration.

Example 149D: Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound of Formula (I), (II), (III), or (IV) is mixed with 50 mgof anhydrous citric acid and 100 mL of 0.9% sodium chloride solution.The mixture is incorporated into an inhalation delivery unit, such as anebulizer, which is suitable for inhalation administration.

Example 149E: Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of acompound of Formula (I), (II), (III), or (IV) is mixed with 2.5 g ofmethylcellulose (1500 mPa), 100 mg of methylparaben, 5 g of glycerin and100 mL of purified water. The resulting gel mixture is then incorporatedinto rectal delivery units, such as syringes, which are suitable forrectal administration.

Example 149F: Suppository Formulation

A suppository of total weight 2.5 g is prepared by mixing a compound ofFormula (I), (II), (III), or (IV) with Witepsol™ H-15 (triglycerides ofsaturated vegetable fatty acid; Riches-Nelson, Inc., New York), and hasthe following composition:

Quantity per Ingredient suppository, mg compound of Formula (I), (II),(III), or (IV) 500 Witepsol ® H-15 balance

Example 149G: Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound of Formula (I), (II), (III), or (IV) is mixed with 1.75 g ofhydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropylmyristate and 100 mL of purified alcohol USP. The resulting gel mixtureis then incorporated into containers, such as tubes, which are suitablefor topical administration.

Example 149H: Ophthalmic Solution Composition

To prepare a pharmaceutical opthalmic solution composition, 100 mg of acompound of Formula (I), (II), (III), or (IV) is mixed with 0.9 g ofNaCl in 100 mL of purified water and filtered using a 0.2 micron filter.The resulting isotonic solution is then incorporated into ophthalmicdelivery units, such as eye drop containers, which are suitable forophthalmic administration.

The examples and embodiments described herein are for illustrativepurposes only and in some embodiments, various modifications or changesare to be included within the purview of disclosure and scope of theappended claims.

What is claimed is:
 1. A compound of Formula (III):

wherein: each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃,—OCH₂F, —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,—S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(RS)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl, substitutedor unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl; R₂ and R₃ are each independently H,—CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃are taken together to form a 5- or 6-membered heterocyclic ring; R₄ andR₅ are independently H, halogen, —CN, —OH, —CF₃, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₉heteroaryl; R₆ is H, unsubstituted C₁-C₆alkyl,—(C(R₁₄)(R₁₅))_(m)R₁₇, —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂),—(C(R₁₄)(R₁₅))_(m)OR₁₃, —(C(R₁₄)(R₁₅))_(n)R₁₆, or —OR₂₂; R₇ issubstituted or unsubstituted phenoxy or —C(═O)R₂₃; each R₈ isindependently H or substituted or unsubstituted C₁-C₆alkyl; each R₉ isindependently substituted or unsubstituted C₁-C₆alkyl; R₁₀ is H orunsubstituted C₁-C₄alkyl; Rn is H, substituted or unsubstitutedC₁-C₆alkyl, —C(═O)R₁₉, or —S(═O)₂R₁₉; R₁₂ is H or substituted orunsubstituted C₁-C₆alkyl; R₁₃ is H or substituted or unsubstitutedC₁-C₆alkyl; each R₁₄ and R₁₅ is each independently H, halogen, orsubstituted or unsubstituted C₁-C₆alkyl; R₁₆ is substituted orunsubstituted C₂-C₇heterocycloalkyl or —C(═O)N(R₁₈)₂; R₁₇ is —C(═O)R₂₀,—CO₂R₂₁, —C(═O)N(R₂₁)₂, or substituted or unsubstituted C₂-C₉heteroaryl;each R₁₈ is independently H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₂-C₇heterocycloalkyl, or substituted orunsubstituted C₃-C₈cycloalkyl; or two R₁₈ are taken together to form aheterocycloalkyl ring; R₁₉ is substituted or unsubstituted C₁-C₆alkyl;R₂₀ is substituted or unsubstituted C₁-C₆alkyl; each R₂₁ isindependently H, or substituted or unsubstituted C₁-C₆alkyl; or two R₂₁are taken together to form a heterocycloalkyl ring; R₂₂ is H, orsubstituted or unsubstituted C₁-C₆alkyl; R₂₃ is substituted orunsubstituted C₆-C₁₀aryl; m is 2-6; n is 1-5; and p is 0-4; or apharmaceutically acceptable salt or solvate thereof.
 2. The compound ofclaim 1, wherein R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl.
 3. The compound of claim 1,wherein R₅ is H.
 4. The compound of claim 1, wherein R₄ is halogen, —CN,—OH, —CF₃, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkoxy, substituted or unsubstitutedC₁-C₆heteroalkyl.
 5. The compound of claim 1, wherein R₁₀ is H.
 6. Thecompound of claim 1, wherein R₇ is substituted or unsubstituted phenoxy.7. The compound of claim 1, wherein R₇ is —C(═O)R₂₃.
 8. The compound ofclaim 1, wherein R₄ is substituted or unsubstituted C₁-C₆alkyl.
 9. Thecompound of claim 8, wherein C₁-C₆alkyl is methyl.
 10. The compound ofclaim 1, wherein p is
 2. 11. The compound of claim 1, wherein R₆ is—C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂).
 12. The compound of claim 1, wherein thecompound is selected from:

pharmaceutically acceptable salt or solvate thereof.
 13. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt or solvate thereof, and at least onepharmaceutically acceptable excipient.
 14. A method for treating adisease in a subject comprising administering to the subject in needthereof a composition comprising a compound of claim 1, or apharmaceutically acceptable salt or solvate thereof; wherein the diseaseis cancer or Down's Syndrome, and wherein the cancer is brain cancer,glioblastoma multiforme, medulloblastoma, astrocytomas, brain stemgliomas, meningiomas, oligodendrogliomas, melanoma, lung cancer, breastcancer, or leukemia.
 15. The method of claim 14, wherein the disease isDown's Syndrome.